rs115611153

chr2-70214430-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.44

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]

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

ACMG classification

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 GnomAd at 1046 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIA1	NM_022173.4	c.953A>G	p.Gln318Arg	missense_variant	12/13	ENST00000433529.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIA1	ENST00000433529.7	c.953A>G	p.Gln318Arg	missense_variant	12/13	2	NM_022173.4	P4

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1046 AN: 152150 Hom.: 6 Cov.: 32

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.: 9 AF XY: 0.00671 AC XY: 912 AN XY: 135838

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.: 90 Cov.: 31 AF XY: 0.0100 AC XY: 7273 AN XY: 727154

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.: 6 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74444

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.: 14

Bravo AF: 0.00671

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0123 AC: 106

ExAC AF: 0.00631 AC: 766

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TIA1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

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

Welander distal myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
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	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
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	T
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

Other links and lift over

dbSNP: rs115611153; hg19: chr2-70441562; COSMIC: COSV99031395; COSMIC: COSV99031395;