9-95099836-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• 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, single submitter B:1
• Conservation: PhyloP100: -0.282

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-95099836-C-T is Benign according to our data. Variant chr9-95099836-C-T is described in ClinVar as [Benign]. Clinvar id is 367581.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
FANCC	NM_000136.3	c.*1871G>A		3_prime_UTR_variant	15/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.*1871G>A		3_prime_UTR_variant	15/15	1	NM_000136.3	P1
FANCC	ENST00000375305.6	c.*1871G>A		3_prime_UTR_variant	15/15	1		P1
FANCC	ENST00000696260.1	n.4363G>A		non_coding_transcript_exon_variant	3/3
AOPEP	ENST00000710812.1	n.410+19056C>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.487

Gnomad4 ASJ exome AF: 0.306

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.434

Gnomad4 FIN exome AF: 0.543

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.395

Alfa AF: 0.372 Hom.: 2850

Bravo AF: 0.369

Asia WGS AF: 0.480 AC: 1666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group C Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.88
Dann	Benign	0.46

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: rs4647558; hg19: chr9-97862118;