rs112446681

Positions:

• chr9-95111288-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000490972.7(FANCC):​c.1387C>T​(p.Arg463Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,569,554 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: FANCC ENST00000490972.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.505

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038080513).
• BP6: Variant 9-95111288-G-A is Benign according to our data. Variant chr9-95111288-G-A is described in ClinVar as [Benign]. Clinvar id is 134308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95111288-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00378 (576/152298) while in subpopulation AFR AF= 0.0134 (555/41564). AF 95% confidence interval is 0.0124. There are 3 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.1329+175C>T		intron_variant		ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.1329+175C>T		intron_variant		1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152182 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000976 AC: 177 AN: 181306 Hom.: 0 AF XY: 0.000727 AC XY: 73 AN XY: 100456

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000754

Gnomad FIN exome AF: 0.000594

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.000509 AC: 721 AN: 1417256 Hom.: 6 Cov.: 37 AF XY: 0.000472 AC XY: 332 AN XY: 703136

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.000882

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000965

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152298 Hom.: 3 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74464

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00417

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00100 AC: 118

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 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. -

Fanconi anemia Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 10, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

FANCC: BS1, BS2 -

Fanconi anemia complementation group C Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.87
DANN	Benign	0.48
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0038	T
MutationTaster	Benign	1.0	N;N
Sift4G	Benign	0.090	T
Vest4		0.086
MVP		0.80
GERP RS		-2.8

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

Other links and lift over

dbSNP: rs112446681; hg19: chr9-97873570;