5-157162649-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_130899.3(GARIN3):c.1616G>A(p.Arg539Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,138 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: GARIN3 NM_130899.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.203

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002883494).
• BP6: Variant 5-157162649-C-T is Benign according to our data. Variant chr5-157162649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2655990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00316 (4626/1461890) while in subpopulation MID AF= 0.0229 (132/5768). AF 95% confidence interval is 0.0197. There are 20 homozygotes in gnomad4_exome. There are 2397 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARIN3	NM_130899.3	c.1616G>A	p.Arg539Lys	missense_variant	2/2	ENST00000302938.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARIN3	ENST00000302938.4	c.1616G>A	p.Arg539Lys	missense_variant	2/2	1	NM_130899.3	P1
ITK	ENST00000521769.5	c.-296-3439C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152130 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00299 AC: 752 AN: 251268 Hom.: 4 AF XY: 0.00341 AC XY: 463 AN XY: 135792

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00433

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00316 AC: 4626 AN: 1461890 Hom.: 20 Cov.: 33 AF XY: 0.00330 AC XY: 2397 AN XY: 727248

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00335

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152248 Hom.: 1 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74436

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00432

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00427 Hom.: 3

Bravo AF: 0.00294

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00315 AC: 383

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00747

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

GARIN3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.94
Dann	Benign	0.87
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.072
Sift	Benign	0.040	D
Sift4G	Uncertain	0.049	D
Polyphen		0.43	B
Vest4		0.11
MVP		0.28
MPC		0.11
ClinPred		0.0026	T
GERP RS		-0.24
Varity_R		0.12
gMVP		0.35

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: rs147753755; hg19: chr5-156589660; COSMIC: COSV99074228; COSMIC: COSV99074228;