7-8138843-C-T

Position:

• chr7-8138843-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136020.3(ICA1):​c.1057G>A​(p.Gly353Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICA1 NM_001136020.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

Genes affected

ICA1 (HGNC:5343): (islet cell autoantigen 1) This gene encodes a protein with an arfaptin homology domain that is found both in the cytosol and as membrane-bound form on the Golgi complex and immature secretory granules. This protein is believed to be an autoantigen in insulin-dependent diabetes mellitus and primary Sjogren's syndrome. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

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=0.06998375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICA1	NM_001136020.3	c.1057G>A	p.Gly353Ser	missense_variant	12/14	ENST00000402384.8	NP_001129492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICA1	ENST00000402384.8	c.1057G>A	p.Gly353Ser	missense_variant	12/14	2	NM_001136020.3	ENSP00000385570	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

The c.1057G>A (p.G353S) alteration is located in exon 12 (coding exon 11) of the ICA1 gene. This alteration results from a G to A substitution at nucleotide position 1057, causing the glycine (G) at amino acid position 353 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Benign	0.71
DEOGEN2	Benign	0.11	T;T;.;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.61	.;T;T;.;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.75	N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.78	T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.023	B;B;.;B;B;.
Vest4		0.070
MutPred		0.50		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);.;.;
MVP		0.62
MPC		0.14
ClinPred		0.14	T
GERP RS		2.9
Varity_R		0.028
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-8178473;