rs1800367

Positions:

chr9-95107254-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000136.3(FANCC):c.1345G>A(p.Val449Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,862 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 123 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 101 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.06

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:

FANCC (HGNC:):

FANCC 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=0.0033890307).

BP6

Variant 9-95107254-C-T is Benign according to our data. Variant chr9-95107254-C-T is described in ClinVar as [Benign]. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3 linkuse as main transcript	c.1345G>A	p.Val449Met	missense_variant	14/15	ENST00000289081.8	NP_000127.2	Q00597A0A024R9N2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 linkuse as main transcript	c.1345G>A	p.Val449Met	missense_variant	14/15	1	NM_000136.3	ENSP00000289081.3		Q00597

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3169

AN:

152126

Hom.:

123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0722

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00609

AC:

1527

AN:

250656

Hom.:

AF XY:

0.00459

AC XY:

622

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.0754

Gnomad AMR exome

AF:

0.00446

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.00425

GnomAD4 exome

AF:

0.00246

AC:

3598

AN:

1461618

Hom.:

101

Cov.:

AF XY:

0.00214

AC XY:

1557

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0719

Gnomad4 AMR exome

AF:

0.00463

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000453

Gnomad4 OTH exome

AF:

0.00548

GnomAD4 genome

AF:

0.0209

AC:

3180

AN:

152244

Hom.:

123

Cov.:

AF XY:

0.0196

AC XY:

1462

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0723

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00455

Hom.:

Bravo

AF:

0.0239

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0760

AC:

335

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00746

AC:

906

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000949

ClinVar

Significance: Benign

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2016	Variant summary: The c. variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a neutral outcome. The variant is present in the control population dataset of ExAC at frequency of 0.78%, predomintantly observed in the African subpopulation at a frequency of 8%, including 37 homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.18%, strong evidence that it is a benign polymorphism. Classification of the variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30967997, 28135048, 24728327) -

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2016	- -

Fanconi anemia

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -

Fanconi anemia complementation group C

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The FANCC p.Val449Met variant was identified in 4 of 912 proband chromosomes (frequency: 0.004) from British/other individuals or families with non-BRCA1/2 breast cancer, Fanconi anemia and leukemia, and was identified in 8 of 1362 control chromosomes from healthy individuals (Gibson 1996, Seal 2003, Barber 2003, Bodian 2014). The variant was also identified in dbSNP (ID: rs1800367) â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Prevention Genetics and Invitae; likely benign by Illumina, and unclassified by ITMI), Clinvitae (2X), LOVD 3.0 (1X) but was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 2071 (76 homozygous) of 276492 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017) being identified in the following population at a frequency greater than 1%: African in 1753 (74 homozygous) of 23978 chromosomes (freq: 0.07), The p.Val449 residue is not conserved in mammals and 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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2016

This alteration is classified as 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

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.79

.;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.080

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.99

D;D

Vest4

0.41

MVP

0.57

MPC

0.27

ClinPred

0.015

GERP RS

1.6

Varity_R

0.052

gMVP

0.26

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