chr2-70215379-C-A

Variant names:

• chr2-70215379-C-A
• rs144296151
• NM_022173.4:c.880G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022173.4(TIA1):​c.880G>T​(p.Val294Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V294M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TIA1 NM_022173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283
• Publications: 6 publications found

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

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=0.12547705).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	NM_022173.4	MANE Select	c.880G>T	p.Val294Leu	missense	Exon 11 of 13	NP_071505.2	P31483-1
	TIA1	NM_001351508.2		c.880G>T	p.Val294Leu	missense	Exon 11 of 13	NP_001338437.1	F8W8I6
	TIA1	NM_001351509.2		c.853G>T	p.Val285Leu	missense	Exon 10 of 12	NP_001338438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	ENST00000433529.7	TSL:2 MANE Select	c.880G>T	p.Val294Leu	missense	Exon 11 of 13	ENSP00000401371.2	P31483-1
	TIA1	ENST00000415783.6	TSL:1	c.847G>T	p.Val283Leu	missense	Exon 10 of 12	ENSP00000404023.2	P31483-2
	TIA1	ENST00000881363.1		c.976G>T	p.Val326Leu	missense	Exon 12 of 14	ENSP00000551422.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251268 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461634 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Welander distal myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.28
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.19
Sift	Benign	0.61	T
Sift4G	Benign	0.67	T
Polyphen		0.014	B
Vest4		0.22
MutPred		0.40		Gain of catalytic residue at V294 (P = 0.2051)
MVP		0.34
MPC		0.56
ClinPred		0.29	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.38
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs144296151; hg19: chr2-70442511;