9-95099836-C-T

Variant names:

• chr9-95099836-C-T
• rs4647558
• NM_000136.3:c.*1871G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000136.3(FANCC):​c.*1871G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 232,466 control chromosomes in the GnomAD database, including 18,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (11349 hom., cov: 32)
  • Exomes 𝑓: 0.41 (7129 hom.)
• Consequence: FANCC NM_000136.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.282
• Publications: 16 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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.*1871G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.*1871G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_000136.3	ENSP00000289081.3
FANCC	ENST00000375305.6	c.*1871G>A		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000364454.1
FANCC	ENST00000696260.1	n.4363G>A		non_coding_transcript_exon_variant	Exon 3 of 3
AOPEP	ENST00000710812.1	n.410+19056C>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57055 AN: 151922 Hom.: 11343 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.410 AC: 32979 AN: 80426 Hom.: 7129 Cov.: 0 AF XY: 0.406 AC XY: 15095 AN XY: 37210

African (AFR) AF: 0.240 AC: 919 AN: 3834

American (AMR) AF: 0.487 AC: 1194 AN: 2454

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1555 AN: 5074

East Asian (EAS) AF: 0.566 AC: 6389 AN: 11286

South Asian (SAS) AF: 0.434 AC: 307 AN: 708

European-Finnish (FIN) AF: 0.543 AC: 50 AN: 92

Middle Eastern (MID) AF: 0.343 AC: 170 AN: 496

European-Non Finnish (NFE) AF: 0.399 AC: 19884 AN: 49788

Other (OTH) AF: 0.375 AC: 2511 AN: 6694

GnomAD4 genome AF: 0.375 AC: 57067 AN: 152040 Hom.: 11349 Cov.: 32 AF XY: 0.382 AC XY: 28393 AN XY: 74324

African (AFR) AF: 0.237 AC: 9818 AN: 41490

American (AMR) AF: 0.473 AC: 7229 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1052 AN: 3468

East Asian (EAS) AF: 0.566 AC: 2907 AN: 5140

South Asian (SAS) AF: 0.455 AC: 2189 AN: 4816

European-Finnish (FIN) AF: 0.461 AC: 4878 AN: 10584

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27626 AN: 67946

Other (OTH) AF: 0.395 AC: 836 AN: 2114

Alfa AF: 0.380 Hom.: 4591

Bravo AF: 0.369

Asia WGS AF: 0.480 AC: 1666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Benign:1

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.88
DANN	Benign	0.46
PhyloP100		-0.28
Mutation Taster		=100/0	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: rs4647558; hg19: chr9-97862118;