NM_000136.3:c.*2164G>T

Variant names:

• chr9-95099543-C-A
• rs566582636
• NM_000136.3:c.*2164G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000136.3(FANCC):​c.*2164G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 230,274 control chromosomes in the GnomAD database, including 1 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 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: FANCC NM_000136.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.188
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.*2164G>T		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.*2164G>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_000136.3	ENSP00000289081.3
FANCC	ENST00000375305.6	c.*2164G>T		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000364454.1
FANCC	ENST00000696260.1	n.4656G>T		non_coding_transcript_exon_variant	Exon 3 of 3
AOPEP	ENST00000710812.1	n.410+18763C>A		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 151666 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000751

Gnomad OTH AF: 0.00290

GnomAD4 exome AF: 0.000382 AC: 30 AN: 78490 Hom.: 0 Cov.: 0 AF XY: 0.000332 AC XY: 12 AN XY: 36134

African (AFR) AF: 0.00 AC: 0 AN: 3720

American (AMR) AF: 0.000417 AC: 1 AN: 2396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4964

East Asian (EAS) AF: 0.00 AC: 0 AN: 11152

South Asian (SAS) AF: 0.00 AC: 0 AN: 694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 480

European-Non Finnish (NFE) AF: 0.000495 AC: 24 AN: 48474

Other (OTH) AF: 0.000764 AC: 5 AN: 6544

GnomAD4 genome AF: 0.00118 AC: 179 AN: 151784 Hom.: 1 Cov.: 31 AF XY: 0.00169 AC XY: 125 AN XY: 74154

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.000525 AC: 8 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000751 AC: 51 AN: 67904

Other (OTH) AF: 0.00287 AC: 6 AN: 2094

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.000442

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group C Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.45
DANN	Benign	0.43
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

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: rs566582636; hg19: chr9-97861825;