rs606231256

Positions:

• chr16-30188371-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000219150.10(CORO1A):​c.1078del​(p.Gln360ArgfsTer45) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CORO1A ENST00000219150.10 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.11

Genes affected

CORO1A (HGNC:2252): (coronin 1A) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. A related pseudogene has been defined on chromosome 16. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30188371-TC-T is Pathogenic according to our data. Variant chr16-30188371-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 157509.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-30188371-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CORO1A	NM_007074.4	c.1078del	p.Gln360ArgfsTer45	frameshift_variant	10/11	ENST00000219150.10	NP_009005.1
CORO1A	NM_001193333.3	c.1078del	p.Gln360ArgfsTer45	frameshift_variant	11/12		NP_001180262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CORO1A	ENST00000219150.10	c.1078del	p.Gln360ArgfsTer45	frameshift_variant	10/11	1	NM_007074.4	ENSP00000219150	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461588 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to CORO1A deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 08, 2018	Loss-of-function variants in CORO1A are known to be pathogenic (PMID: 18836449, 25073507). This variant has been observed to segregate with combined immunodeficiency and selective T cell deficiency in a family (PMID: 25073507). This variant is also known as c.1077delC in the literature. ClinVar contains an entry for this variant (Variation ID: 157509). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln360Argfs*45) in the CORO1A gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231256; hg19: chr16-30199692;