rs115611153

Positions:

chr2-70214430-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_022173.4(TIA1):c.953A>G(p.Gln318Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,613,990 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 90 hom. )

Consequence

TIA1
NM_022173.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.44

Variant links:

Genes affected

TIA1 (HGNC:11802): (TIA1 cytotoxic granule associated RNA binding protein) The product encoded by this gene is a member of a RNA-binding protein family and possesses nucleolytic activity against cytotoxic lymphocyte (CTL) target cells. It has been suggested that this protein may be involved in the induction of apoptosis as it preferentially recognizes poly(A) homopolymers and induces DNA fragmentation in CTL targets. The major granule-associated species is a 15-kDa protein that is thought to be derived from the carboxyl terminus of the 40-kDa product by proteolytic processing. Alternative splicing resulting in different isoforms has been found for this gene. [provided by RefSeq, May 2017]

TIA1 links:

TIA1 (HGNC:):

TIA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006985873).

BP6

Variant 2-70214430-T-C is Benign according to our data. Variant chr2-70214430-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70214430-T-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1046 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIA1	NM_022173.4 linkuse as main transcript	c.953A>G	p.Gln318Arg	missense_variant	12/13	ENST00000433529.7	NP_071505.2	P31483-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIA1	ENST00000433529.7 linkuse as main transcript	c.953A>G	p.Gln318Arg	missense_variant	12/13	2	NM_022173.4	ENSP00000401371.2		P31483-1

Frequencies

GnomAD3 genomes

AF:

0.00687

AC:

1046

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00650

AC:

1633

AN:

251346

Hom.:

AF XY:

0.00671

AC XY:

912

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00565

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.0101

AC:

14738

AN:

1461722

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

7273

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00555

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00562

Gnomad4 FIN exome

AF:

0.00137

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00828

GnomAD4 genome

AF:

0.00687

AC:

1046

AN:

152268

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00560

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00671

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0123

AC:

106

ExAC

AF:

0.00631

AC:

766

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0102

EpiControl

AF:

0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TIA1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	See Variant Classification Assertion Criteria. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Welander distal myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.095

Sift

Benign

0.039

D;D;D;D

Sift4G

Benign

0.32

T;T;T;.

Polyphen

0.26

B;P;.;.

Vest4

0.61

MVP

0.60

MPC

1.2

ClinPred

0.012

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.79

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

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