rs55719336

chr9-95135373-G-Achr9-95135373-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000136.3(FANCC):c.816C>T(p.Ile272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,613,888 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I272I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00094 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (7 hom.)
• Consequence: FANCC NM_000136.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -0.472

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-95135373-G-A is Benign according to our data. Variant chr9-95135373-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95135373-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.472 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00094 (143/152148) while in subpopulation EAS AF= 0.0131 (68/5178). AF 95% confidence interval is 0.0106. There are 2 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.816C>T	p.Ile272=	synonymous_variant	8/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.816C>T	p.Ile272=	synonymous_variant	8/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.000941 AC: 143 AN: 152030 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00130 AC: 326 AN: 251432 Hom.: 2 AF XY: 0.00119 AC XY: 162 AN XY: 135896

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1461740 Hom.: 7 Cov.: 31 AF XY: 0.000369 AC XY: 268 AN XY: 727162

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00733

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152148 Hom.: 2 Cov.: 33 AF XY: 0.000995 AC XY: 74 AN XY: 74368

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000979

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCC p.Ile272= variant was identified in 1 of 1038 proband chromosomes (frequency: 0.001) from individuals or families with pancreatic and breast cancers and was present in 1 of 1316 control chromosomes (frequency: 0.001) from healthy individuals (Couch 2005, Seal 2003). The variant was also identified in dbSNP (ID: rs55719336) as “with other allele”; in ClinVar and Clinvitae databases as benign by GeneDx and Invitae, and as uncertain significance by Illumina Clinical Serivices; and in LOVD 3.0 database with no classification provided. Furthermore, the variant was also identified in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004) and in the NHLBI GO Exome Sequencing Project in 9 of 4406 African American alleles. The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 339 (4 homozygous) of 277168 chromosomes at a frequency of 0.001 in the following populations: African in 31 of 24028 chromosomes (freq. 0.001), Latino in 2 of 34412 chromosomes (freq. 0.00006), European Non-Finnish in 1 of 126670 chromosomes (freq. 0.00001), East Asian in 291 of 18864 chromosomes (freq. 0.02), South Asian in 10 of 30780 chromosomes (freq. 0.0003), and in other in 4 of 6468 chromosomes (freq. 0.001) but was not seen in Ashkenazi Jewish and European Finnish populations (Genome Aggregation Consortium Feb 27, 2017). The p.Ile272= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -

not provided Uncertain:1 Benign:2

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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FANCC: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2016	Variant summary: The FANCC c.816C>T (p.Ile272Ile) variant affects a non-conserved nucleotide, resulting in a synonymous mutation. Mutation taster predicts damaging outcome for this variant while 5/5 in silico tools via Alamut predict the variant not to have an impact on normal splicing. The variant was observed by the ExAC project in 159/121094 control chromosomes (1 homozygote) at a frequency of 0.001313, which does not exceed maximal expected frequency of a pathogenic allele (0.0017678). However, in the East Asian subcohort, the variant was observed at an allele frequency of 0.015 which exceeds the estimated maximal expected allele frequency of a disease causing FANCC allele indicating the variant to be a neutral polymorphism in populations of East Asian origin. In addition, two independent clinical laboratory databases classified this variant as Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the East Asian population, it was classified as Benign. -

Fanconi anemia Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

FANCC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 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). -

Fanconi anemia complementation group C Benign:1

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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2016

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
BayesDel_noAF	Benign	-0.37
Cadd	Benign	6.0
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55719336; hg19: chr9-97897655; COSMIC: COSV104610642;