9-95107254-C-T

Variant names:

• chr9-95107254-C-T
• rs1800367
• NM_000136.3:c.1345G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V449A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (123 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (101 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:1
• Conservation: PhyloP100: 1.06
• Publications: 20 publications found

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]

LOC107987102 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar as Benign. Clinvar id is 134298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95107254-C-T is described in CliVar 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 rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.1345G>A	p.Val449Met	missense_variant	Exon 14 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.1345G>A	p.Val449Met	missense_variant	Exon 14 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3169 AN: 152126 Hom.: 123 Cov.: 33

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

GnomAD2 exomes AF: 0.00609 AC: 1527 AN: 250656 AF XY: 0.00459

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 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.: 32 AF XY: 0.00214 AC XY: 1557 AN XY: 727110

African (AFR) AF: 0.0719 AC: 2407 AN: 33470

American (AMR) AF: 0.00463 AC: 207 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26134

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86208

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00495 AC: 28 AN: 5654

European-Non Finnish (NFE) AF: 0.000453 AC: 504 AN: 1111966

Other (OTH) AF: 0.00548 AC: 331 AN: 60384

GnomAD4 genome AF: 0.0209 AC: 3180 AN: 152244 Hom.: 123 Cov.: 33 AF XY: 0.0196 AC XY: 1462 AN XY: 74440

African (AFR) AF: 0.0723 AC: 3001 AN: 41514

American (AMR) AF: 0.00660 AC: 101 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68020

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00833 Hom.: 107

Bravo AF: 0.0239

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0760 AC: 335

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000949

ClinVar

Significance: Benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30967997, 28135048, 24728327) -

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. 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. -

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:3 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:3

May 10, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 06, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group C Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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.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) “With other allele”, 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

Sep 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.79	.;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PhyloP100		1.1
PrimateAI	Benign	0.35	T
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	T
GERP RS		1.6
Varity_R		0.052
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800367; hg19: chr9-97869536; COSMIC: COSV56660124;