rs31208

Variant names:

• chr5-157162574-A-G
• rs31208
• NM_130899.3:c.1691T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 20 publications found

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]

ITK Gene-Disease associations (from GenCC):

• lymphoproliferative syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• lymphoproliferative syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130899.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARIN3	NM_130899.3	MANE Select	c.1691T>C	p.Met564Thr	missense	Exon 2 of 2	NP_570969.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARIN3	ENST00000302938.4	TSL:1 MANE Select	c.1691T>C	p.Met564Thr	missense	Exon 2 of 2	ENSP00000305596.4
	ITK	ENST00000521769.5	TSL:4	c.-296-3514A>G		intron	N/A	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

GnomAD2 exomes AF: 0.108 AC: 27154 AN: 251270 AF XY: 0.106

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 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

African (AFR) AF: 0.241 AC: 8071 AN: 33480

American (AMR) AF: 0.0683 AC: 3053 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2871 AN: 26136

East Asian (EAS) AF: 0.0158 AC: 628 AN: 39700

South Asian (SAS) AF: 0.0646 AC: 5576 AN: 86258

European-Finnish (FIN) AF: 0.105 AC: 5618 AN: 53414

Middle Eastern (MID) AF: 0.157 AC: 903 AN: 5768

European-Non Finnish (NFE) AF: 0.132 AC: 146726 AN: 1112006

Other (OTH) AF: 0.121 AC: 7286 AN: 60396

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

African (AFR) AF: 0.239 AC: 9906 AN: 41386

American (AMR) AF: 0.0963 AC: 1472 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 369 AN: 3464

East Asian (EAS) AF: 0.0136 AC: 70 AN: 5158

South Asian (SAS) AF: 0.0535 AC: 257 AN: 4800

European-Finnish (FIN) AF: 0.0902 AC: 952 AN: 10560

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8954 AN: 67952

Other (OTH) AF: 0.138 AC: 293 AN: 2116

Alfa AF: 0.134 Hom.: 7504

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 v4.9

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
PhyloP100		0.18
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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