rs116621885

chr2-70212810-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 2.02

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 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 0 benign (100%) in NM_022173.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008425117).
• BS2: High AC in GnomAd at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIA1	NM_022173.4	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	c.1070A>G	p.Asn357Ser	missense_variant	13/13	2	NM_022173.4	P4

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152144 Hom.: 6 Cov.: 32

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.: 17 AF XY: 0.00696 AC XY: 946 AN XY: 135884

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.: 70 Cov.: 30 AF XY: 0.00758 AC XY: 5515 AN XY: 727170

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.: 6 Cov.: 32 AF XY: 0.00544 AC XY: 405 AN XY: 74440

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.: 9

Bravo AF: 0.00485

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00988 AC: 85

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00842

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TIA1: BP4, BS2 -
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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 05, 2023	BP4 -

TIA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2023

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
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	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.48	T
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	T
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

Other links and lift over

dbSNP: rs116621885; hg19: chr2-70439942; COSMIC: COSV57006569; COSMIC: COSV57006569;