rs1800368

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000136.3(FANCC):c.1394A>G(p.Gln465Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000643 in 1,614,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13O:1

Conservation

PhyloP100: -1.73

Variant links:

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

FANCC links:

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

AOPEP links:

LOC107987102 (HGNC:):

LOC107987102 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003341049).

BP6

Variant 9-95107205-T-C is Benign according to our data. Variant chr9-95107205-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 134297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00326 (497/152316) while in subpopulation AFR AF= 0.0111 (461/41570). AF 95% confidence interval is 0.0103. There are 0 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3 link	c.1394A>G	p.Gln465Arg	missense_variant	Exon 14 of 15	ENST00000289081.8	NP_000127.2	Q00597A0A024R9N2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 link	c.1394A>G	p.Gln465Arg	missense_variant	Exon 14 of 15	1	NM_000136.3	ENSP00000289081.3		Q00597

Frequencies

GnomAD3 genomes

AF:

0.00327

AC:

498

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.000828

AC:

208

AN:

251264

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000370

AC:

541

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00326

AC:

497

AN:

152316

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.000575

Hom.:

Bravo

AF:

0.00339

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000980

AC:

119

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCC: BP4, BS1 -

Feb 28, 2020

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Apr 29, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1394A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Arg. 5/5 in-silico tools predict benign outcome for this variant. This variant is found in 120/120326 control chromosomes at a frequency of 0.0009973, predominantly observed in African subpopulation in ExAC with observed MAF of 1%. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0017678), suggesting this variant is likely a benign polymorphism especially for Africans. This variant has been reported in the literature (Gibson_1996) in both cohorts of affected and control individuals and was classified by authors as a polymorphism. One patients unaffected parent who was obligated heterozygous carrier was genotyped to be homozygote for this variant, further supporting the neutral effect of this variant. In addition, multiple clinical laboratory/reputable database classified this variant as benign/likely benign, without evidence to independently evaluate. Taken together, the variant was classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:3Other:1

Jan 08, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 05, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Fanconi anemia complementation group C

Benign:3

Apr 12, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Fanconi anemia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A

Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC p.Gln465Arg variant was identified in 1 of 194 proband chromosomes (frequency: 0.01546) from individuals or families with Fanconi Anemia (Gibson_1996_8844212). In this study of Fanconi Anemia patients, the p.Gln465Arg variant was also found to be homozygous in an unaffected individual, and was classified by the authors as a polymorphism (Gibson_1996_8844212). The variant was also identified in dbSNP (ID: rs1800368) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (as benign by GeneDx, Invitae, and Laboratory Corporation of America, and as likely benign by Genetic Services Laboratory University of Chicago, and Ambry Genetics), Clinvitae (as in ClinVar), and LOVD 3.0 databases. The variant was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 301 of 277086 chromosomes at a frequency of 0.001086 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 261 of 24026 chromosomes (freq: 0.01086), Other in 2 of 6458 chromosomes (freq: 0.00031), Latino in 25 of 34414 chromosomes (freq: 0.000726), European (Non-Finnish) in 4 of 126630 chromosomes (freq: 0.000032), and South Asian in 9 of 30764 chromosomes (freq: 0.000293), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Gln465 residue is not conserved in mammals and the variant amino acid Arginine (Arg) is present in Rhesus macaques, increasing the likelihood that this variant does not have clinical significance. In addition, 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 05, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.016

DANN

Benign

0.25

DEOGEN2

Benign

0.052

T;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.17

.;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.76

N;N

REVEL

Benign

0.026

Sift

Benign

0.90

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.022

MVP

0.35

MPC

0.055

ClinPred

0.00080

GERP RS

-9.1

Varity_R

0.017

gMVP

0.034

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over