16-30185232-C-T

Position:

• chr16-30185232-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_007074.4(CORO1A):​c.23C>T​(p.Ser8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CORO1A NM_007074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.715

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35050732).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000274 (40/1461814) while in subpopulation NFE AF= 0.0000324 (36/1111992). AF 95% confidence interval is 0.0000237. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CORO1A	NM_007074.4	c.23C>T	p.Ser8Phe	missense_variant	2/11	ENST00000219150.10	NP_009005.1
CORO1A	NM_001193333.3	c.23C>T	p.Ser8Phe	missense_variant	3/12		NP_001180262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CORO1A	ENST00000219150.10	c.23C>T	p.Ser8Phe	missense_variant	2/11	1	NM_007074.4	ENSP00000219150	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250756 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

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: 0.0000187

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to CORO1A deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces serine with phenylalanine at codon 8 of the CORO1A protein (p.Ser8Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CORO1A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;D;D;T;.;T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.7	.;.;L;L;.;.;.;.
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.078	T;D;T;T;D;T;D;D
Sift4G	Benign	0.065	T;D;D;D;D;T;T;T
Polyphen		0.017	.;.;B;B;.;.;.;.
Vest4		0.44, 0.45
MutPred		0.59		Loss of disorder (P = 0.0036);.;Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);
MVP		0.75
MPC		1.9
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.50
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs763479989; hg19: chr16-30196553; COSMIC: COSV54631697; COSMIC: COSV54631697;