Variant chr7-8141774-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136020.3(ICA1):c.946A>G(p.Ser316Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ICA1
NM_001136020.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0550

Variant links:

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]

ICA1 links:

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ACMG classification

Classification made for transcript

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=0.06965229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICA1	NM_001136020.3 linkuse as main transcript	c.946A>G	p.Ser316Gly	missense_variant	10/14	ENST00000402384.8	NP_001129492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICA1	ENST00000402384.8 linkuse as main transcript	c.946A>G	p.Ser316Gly	missense_variant	10/14	2	NM_001136020.3	ENSP00000385570	A1	Q05084-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1409960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703122

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

9.32e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.946A>G (p.S316G) alteration is located in exon 10 (coding exon 9) of the ICA1 gene. This alteration results from a A to G substitution at nucleotide position 946, causing the serine (S) at amino acid position 316 to be replaced by a glycine (G). 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

0.063

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.14

T;T;.;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.62

.;T;T;.;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.070

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.87

N;N;N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.32

T;T;T;T;T;T

Sift4G

Benign

0.42

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;B;.

Vest4

0.15

MutPred

0.34

Loss of phosphorylation at S316 (P = 0.0067);Loss of phosphorylation at S316 (P = 0.0067);.;Loss of phosphorylation at S316 (P = 0.0067);.;.;

MVP

0.40

MPC

0.12

ClinPred

0.047

GERP RS

-2.4

Varity_R

0.025

gMVP

0.031

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over