rs116621885

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/21 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

Publications

20 publications found

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

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

BP6

Variant 2-70212810-T-C is Benign according to our data. Variant chr2-70212810-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261567.

BS2

High AC in GnomAd4 at 886 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIA1	NM_022173.4 link	c.1070A>G	p.Asn357Ser	missense_variant	Exon 13 of 13	ENST00000433529.7	NP_071505.2	P31483-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIA1	ENST00000433529.7 link	c.1070A>G	p.Asn357Ser	missense_variant	Exon 13 of 13	2	NM_022173.4	ENSP00000401371.2		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

GnomAD2 exomes

AF:

0.00665

AC:

1673

AN:

251424

AF XY:

0.00696

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 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

African (AFR)

AF:

0.000837

AC:

AN:

33472

American (AMR)

AF:

0.00181

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

291

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00967

AC:

834

AN:

86250

European-Finnish (FIN)

AF:

0.00622

AC:

332

AN:

53404

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00784

AC:

8714

AN:

1111904

Other (OTH)

AF:

0.00749

AC:

452

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

519

1038

1558

2077

2596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00582

AC:

886

AN:

152262

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

405

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41542

American (AMR)

AF:

0.00170

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00851

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00983

AC:

669

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00793

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

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TIA1: BP4, BS2 -

Jun 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Apr 09, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29886022, 29599744, 26627873, 29457785) -

TIA1-related disorder

Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 01, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Welander distal myopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

2.0

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

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over