rs31208

Positions:

• chr5-157162574-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130899.3(GARIN3):​c.1691T>C​(p.Met564Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,814 control chromosomes in the GnomAD database, including 14,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1993 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12090 hom.)
• Consequence: GARIN3 NM_130899.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179

Genes affected

GARIN3 (HGNC:28397): (golgi associated RAB2 interactor family member 3) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ITK (HGNC:6171): (IL2 inducible T cell kinase) This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003587693).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARIN3	NM_130899.3	c.1691T>C	p.Met564Thr	missense_variant	2/2	ENST00000302938.4	NP_570969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARIN3	ENST00000302938.4	c.1691T>C	p.Met564Thr	missense_variant	2/2	1	NM_130899.3	ENSP00000305596.4
ITK	ENST00000521769.5	c.-296-3514A>G		intron_variant		4		ENSP00000430327.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22379 AN: 151814 Hom.: 1989 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.108 AC: 27154 AN: 251270 Hom.: 1814 AF XY: 0.106 AC XY: 14424 AN XY: 135794

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0634

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0111

Gnomad SAS exome AF: 0.0631

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.124 AC: 180732 AN: 1461882 Hom.: 12090 Cov.: 32 AF XY: 0.122 AC XY: 88443 AN XY: 727244

Gnomad4 AFR exome AF: 0.241

Gnomad4 AMR exome AF: 0.0683

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.0646

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.147 AC: 22407 AN: 151932 Hom.: 1993 Cov.: 32 AF XY: 0.140 AC XY: 10414 AN XY: 74248

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0136

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.0902

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.138

Alfa AF: 0.131 Hom.: 3662

Bravo AF: 0.152

TwinsUK AF: 0.139 AC: 517

ALSPAC AF: 0.136 AC: 525

ESP6500AA AF: 0.235 AC: 1034

ESP6500EA AF: 0.135 AC: 1165

ExAC AF: 0.113 AC: 13672

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.086
DANN	Benign	0.69
DEOGEN2	Benign	0.00028	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.6	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0020
MPC		0.11
ClinPred		0.000024	T
GERP RS		0.95
Varity_R		0.029
gMVP		0.035

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: rs31208; hg19: chr5-156589585; COSMIC: COSV57228907; COSMIC: COSV57228907;