ENST00000490972.7:c.1393_1395delCCT

Variant names:

• chr9-95111279-CAGG-C
• rs587778328
• ENST00000490972.7:c.1393_1395delCCT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PM4_Supporting BP6_Moderate

The ENST00000490972.7(FANCC):​c.1393_1395delCCT​(p.Pro465del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,559,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FANCC ENST00000490972.7 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1 O:1
• Conservation: PhyloP100: 0.0340

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000490972.7. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 9-95111279-CAGG-C is Benign according to our data. Variant chr9-95111279-CAGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 134307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.1329+181_1329+183delCCT		intron_variant	Intron 13 of 14	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.1329+181_1329+183delCCT		intron_variant	Intron 13 of 14	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000598 AC: 10 AN: 167142 Hom.: 0 AF XY: 0.0000541 AC XY: 5 AN XY: 92386

Gnomad AFR exome AF: 0.000550

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000393

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000555

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 33 AN: 1407410 Hom.: 0 AF XY: 0.0000158 AC XY: 11 AN XY: 697322

Gnomad4 AFR exome AF: 0.000651

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000732

Gnomad4 OTH exome AF: 0.0000509

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74488

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

FANCC-related disorder Uncertain:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC c.1393_1395delCCT variant is predicted to result in an in-frame deletion (p.Pro465del). In the canonical transcript (NM_000136.3) this variant is intronic (c.1329+181_1329+183delCCT). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.045% of alleles in individuals of African descent in gnomAD and has been interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134307/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group C Benign:1

Feb 23, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

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: rs587778328; hg19: chr9-97873561;