9-95125109-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000136.3(FANCC):c.973G>A(p.Ala325Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,614,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A325V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 3.02

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]

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012224674).
• BP6: Variant 9-95125109-C-T is Benign according to our data. Variant chr9-95125109-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 127550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95125109-C-T is described in Lovd as [Benign]. Variant chr9-95125109-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000341 (52/152316) while in subpopulation EAS AF= 0.00982 (51/5194). AF 95% confidence interval is 0.00767. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.973G>A	p.Ala325Thr	missense_variant	10/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.973G>A	p.Ala325Thr	missense_variant	10/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00980

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000756 AC: 190 AN: 251484 Hom.: 1 AF XY: 0.000714 AC XY: 97 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000251 AC: 367 AN: 1461864 Hom.: 2 Cov.: 31 AF XY: 0.000237 AC XY: 172 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00738

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00982

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000542 Hom.: 1

Bravo AF: 0.000540

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 16, 2017	- -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCC p.Ala325Thr variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs201407189) as “With Likely benign allele”, and in ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx). The variant was identified in control databases in 200 (1 homozygous) of 277248 chromosomes at a frequency of 0.0007 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the East Asian population in 196 of 18870 chromosomes at a frequency greater than 1% (freq: 0.01). The p.Ala325 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	This variant is associated with the following publications: (PMID: 28863211, 28767289) -

Fanconi anemia complementation group C Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 23, 2019

Variant summary: FANCC c.973G>A (p.Ala325Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 251484 control chromosomes, predominantly at a frequency of 0.01 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCC causing Fanconi Anemia Group C phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. In addition, a recent case-control association study involving breast and/or ovarian cancer patients and controls of Chinese ancestry (Pan_2019), found that the variant is not associated with a significant increase in breast/ovarian cancer risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as benign (2x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

FANCC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 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	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.76	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	0.50	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.16	T;T;.
Sift4G	Benign	0.16	T;T;T
Polyphen		0.94	P;P;.
Vest4		0.26
MVP		0.84
MPC		0.15
ClinPred		0.065	T
GERP RS		4.8
Varity_R		0.097
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs201407189; hg19: chr9-97887391; COSMIC: COSV56660779; COSMIC: COSV56660779;