NM_022173.4:c.953A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

8 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 -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 Benign/Likely_benign. ClinVar VariationId is 261569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1046 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022173.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIA1	NM_022173.4	MANE Select	c.953A>G	p.Gln318Arg	missense	Exon 12 of 13	NP_071505.2	P31483-1
TIA1	NM_001351508.2		c.950A>G	p.Gln317Arg	missense	Exon 12 of 13	NP_001338437.1	F8W8I6
TIA1	NM_001351509.2		c.926A>G	p.Gln309Arg	missense	Exon 11 of 12	NP_001338438.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIA1	ENST00000433529.7	TSL:2 MANE Select	c.953A>G	p.Gln318Arg	missense	Exon 12 of 13	ENSP00000401371.2	P31483-1
TIA1	ENST00000415783.6	TSL:1	c.920A>G	p.Gln307Arg	missense	Exon 11 of 12	ENSP00000404023.2	P31483-2
TIA1	ENST00000881363.1		c.1049A>G	p.Gln350Arg	missense	Exon 13 of 14	ENSP00000551422.1

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

GnomAD2 exomes

AF:

0.00650

AC:

1633

AN:

251346

AF XY:

0.00671

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 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

African (AFR)

AF:

0.00155

AC:

AN:

33474

American (AMR)

AF:

0.00300

AC:

134

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00555

AC:

145

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.00562

AC:

485

AN:

86242

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0120

AC:

13338

AN:

1111926

Other (OTH)

AF:

0.00828

AC:

500

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

729

1457

2186

2914

3643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.00687

AC:

1046

AN:

152268

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41570

American (AMR)

AF:

0.00333

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00560

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

807

AN:

68012

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

143

191

239

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:

0.00951

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Welander distal myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

3.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.7

REVEL

Benign

0.095

Sift

Benign

0.039

Sift4G

Benign

0.32

Polyphen

0.26

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

Mutation Taster

=44/56

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over