2-70229320-TAAAAA-TAAAA

Variant names:

• chr2-70229320-TA-T
• rs750862626
• NM_022173.4:c.223-3delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022173.4(TIA1):​c.223-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,007,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.61

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.

• BP6: Variant 2-70229320-TA-T is Benign according to our data. Variant chr2-70229320-TA-T is described in ClinVar as [Benign]. Clinvar id is 448689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0343 (29608/862280) while in subpopulation AMR AF= 0.0461 (1126/24444). AF 95% confidence interval is 0.0439. There are 0 homozygotes in gnomad4_exome. There are 14599 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIA1	NM_022173.4	c.223-3delT		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000433529.7	NP_071505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIA1	ENST00000433529.7	c.223-3delT		splice_region_variant, intron_variant	Intron 3 of 12	2	NM_022173.4	ENSP00000401371.2

Frequencies

GnomAD3 genomes AF: 0.000538 AC: 78 AN: 145064 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000397

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000350

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0343 AC: 29608 AN: 862280 Hom.: 0 Cov.: 30 AF XY: 0.0343 AC XY: 14599 AN XY: 426184

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.0262

Gnomad4 SAS exome AF: 0.0455

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0352

GnomAD4 genome AF: 0.000537 AC: 78 AN: 145120 Hom.: 0 Cov.: 30 AF XY: 0.000525 AC XY: 37 AN XY: 70472

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00110

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000397

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00145

Gnomad4 NFE AF: 0.000350

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 11, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TIA1-related disorder Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Welander distal myopathy Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs750862626; hg19: chr2-70456452;