chr2-70229320-TA-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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
• Publications: 0 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: Benign. The variant received -8 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 VariationId is 448689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	NM_022173.4	MANE Select	c.223-3delT		splice_region intron	N/A	NP_071505.2
	TIA1	NM_001351508.2		c.223-3delT		splice_region intron	N/A	NP_001338437.1
	TIA1	NM_001351509.2		c.229-3delT		splice_region intron	N/A	NP_001338438.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	ENST00000433529.7	TSL:2 MANE Select	c.223-3delT		splice_region intron	N/A	ENSP00000401371.2
	TIA1	ENST00000415783.6	TSL:1	c.223-3delT		splice_region intron	N/A	ENSP00000404023.2
	TIA1	ENST00000416149.6	TSL:1	c.223-3delT		splice_region intron	N/A	ENSP00000413751.2

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

GnomAD2 exomes AF: 0.0598 AC: 6012 AN: 100452 AF XY: 0.0620

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.0826

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0378

Gnomad FIN exome AF: 0.0694

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0657

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0318 AC: 604 AN: 18986

American (AMR) AF: 0.0461 AC: 1126 AN: 24444

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 622 AN: 14236

East Asian (EAS) AF: 0.0262 AC: 573 AN: 21844

South Asian (SAS) AF: 0.0455 AC: 2164 AN: 47544

European-Finnish (FIN) AF: 0.0471 AC: 1446 AN: 30720

Middle Eastern (MID) AF: 0.0271 AC: 94 AN: 3464

European-Non Finnish (NFE) AF: 0.0327 AC: 21770 AN: 666682

Other (OTH) AF: 0.0352 AC: 1209 AN: 34360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000603 AC: 24 AN: 39776

American (AMR) AF: 0.00110 AC: 16 AN: 14576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.000397 AC: 2 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00145 AC: 13 AN: 8984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000350 AC: 23 AN: 65630

Other (OTH) AF: 0.00 AC: 0 AN: 1996

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000753023), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0455 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	TIA1-related disorder (1)
-	-	1	Welander distal myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs750862626; hg19: chr2-70456452; COSMIC: COSV57005642; COSMIC: COSV57005642;