7-8138861-C-T

Position:

• chr7-8138861-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.1039G>A​(p.Asp347Asn) 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=0.157998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICA1	NM_001136020.3	c.1039G>A	p.Asp347Asn	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.1039G>A	p.Asp347Asn	missense_variant	12/14	2	NM_001136020.3	ENSP00000385570	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 06, 2022

The c.1039G>A (p.D347N) 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 1039, causing the aspartic acid (D) at amino acid position 347 to be replaced by an asparagine (N). 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	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	.;T;T;.;T;D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;L;.;L;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.0040	B;B;.;B;B;.
Vest4		0.086
MutPred		0.56		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);.;.;
MVP		0.60
MPC		0.15
ClinPred		0.51	D
GERP RS		3.0
Varity_R		0.051
gMVP		0.11

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: rs917797466; hg19: chr7-8178491;