Genetic Variant TIA1:p.Asp104Gly (chr2-70227822-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022173.4(TIA1):c.311A>G(p.Asp104Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,444,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D104V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TIA1
NM_022173.4 missense, splice_region

Scores

Splicing: ADA: 0.0008376

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26312703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIA1	NM_022173.4 link	c.311A>G	p.Asp104Gly	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000433529.7	NP_071505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIA1	ENST00000433529.7 link	c.311A>G	p.Asp104Gly	missense_variant, splice_region_variant	Exon 6 of 13	2	NM_022173.4	ENSP00000401371.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444744

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718838

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33136

American (AMR)

AF:

0.00

AC:

AN:

43592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25704

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00

AC:

AN:

83450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101338

Other (OTH)

AF:

0.00

AC:

AN:

59556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.092

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.55

N;.;N

PhyloP100

4.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.59

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.56

MutPred

0.23

Loss of stability (P = 0.0348);Loss of stability (P = 0.0348);Loss of stability (P = 0.0348);

MVP

0.85

MPC

0.74

ClinPred

0.51

GERP RS

5.1

Varity_R

0.18

gMVP

0.78

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00084

dbscSNV1_RF

Benign

0.014

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over