2-70215379-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022173.4(TIA1):c.880G>A(p.Val294Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V294L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TIA1 NM_022173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055640876).
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIA1	NM_022173.4	c.880G>A	p.Val294Met	missense_variant	11/13	ENST00000433529.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIA1	ENST00000433529.7	c.880G>A	p.Val294Met	missense_variant	11/13	2	NM_022173.4	P4

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251268 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135816

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461634 Hom.: 0 Cov.: 30 AF XY: 0.000164 AC XY: 119 AN XY: 727120

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74444

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Welander distal myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 28817800). This variant is present in population databases (rs144296151, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 294 of the TIA1 protein (p.Val294Met). ClinVar contains an entry for this variant (Variation ID: 575375). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.14	T;.;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.88	D;D;T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.90	N;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.11	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.31	T;T;T;.
Polyphen		0.084	B;B;.;.
Vest4		0.17
MVP		0.34
MPC		0.57
ClinPred		0.14	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.36

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: rs144296151; hg19: chr2-70442511;