2-70212810-T-C

Position:

chr2-70212810-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_022173.4(TIA1):c.1070A>G(p.Asn357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,613,982 control chromosomes in the GnomAD database, including 76 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 70 hom. )

Consequence

TIA1
NM_022173.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

Conservation

PhyloP100: 2.02

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:

C2orf42 (HGNC:26056): (chromosome 2 open reading frame 42) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

C2orf42 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest Disordered (size 32) in uniprot entity TIA1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_022173.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008425117).

BS2

High AC in GnomAd4 at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIA1	NM_022173.4 linkuse as main transcript	c.1070A>G	p.Asn357Ser	missense_variant	13/13	ENST00000433529.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIA1	ENST00000433529.7 linkuse as main transcript	c.1070A>G	p.Asn357Ser	missense_variant	13/13	2	NM_022173.4	P4	P31483-1

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

886

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00983

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00665

AC:

1673

AN:

251424

Hom.:

AF XY:

0.00696

AC XY:

946

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00947

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.00918

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00737

AC:

10773

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00758

AC XY:

5515

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00181

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00967

Gnomad4 FIN exome

AF:

0.00622

Gnomad4 NFE exome

AF:

0.00784

Gnomad4 OTH exome

AF:

0.00749

GnomAD4 genome

AF:

0.00582

AC:

886

AN:

152262

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

405

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00951

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00851

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.00983

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00840

Hom.:

Bravo

AF:

0.00485

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00988

AC:

ExAC

AF:

0.00709

AC:

861

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00842

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 05, 2023	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	This variant is associated with the following publications: (PMID: 29886022, 29599744, 26627873, 29457785) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TIA1: BP4, BS2 -

TIA1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The TIA1 c.1070A>G variant is predicted to result in the amino acid substitution p.Asn357Ser. This variant has been reported in the heterozygous state in at least 15 individuals to cause a digenically inherited distal myopathy when in the presence of a pathogenic SQSTM1 variant (Evilä et al. 2016. PubMed ID: 26627873; Niu et al. 2018. PubMed ID: 29599744; Lee et al. 2018. PubMed ID: 29457785). Functional studies have shown that the c.1070A>G variant dictates a myodegenerative phenotype by disrupting stress granule homeostasis and ubiquitin-mediated autophagic degradation (Lee et al. 2018. PubMed ID: 29457785). Therefore, the c.1070A>G variant (whether heterozygous or homozygous) is only pathogenic for a myopathy phenotype when co-inherited with a pathogenic SQSTM1 variant. -

Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 24, 2017

- -

Welander distal myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;T;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;.;.

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.69

N;N;N;N

REVEL

Benign

0.086

Sift

Benign

0.77

T;T;T;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

0.22

B;P;.;.

Vest4

0.14

MVP

0.51

MPC

0.45

ClinPred

0.022

GERP RS

5.9

Varity_R

0.13

gMVP

0.78

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