2-70229320-TAAAAA-TAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_022173.4(TIA1):​c.223-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,009,730 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 0.00038 (0 hom., cov: 30)
  • Exomes 𝑓: 0.046 (0 hom.)
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-70229320-T-TA is Benign according to our data. Variant chr2-70229320-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1582154.Status of the report is criteria_provided_single_submitter, 1 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.223-3dupT		splice_region intron	N/A	NP_071505.2
	TIA1	NM_001351508.2		c.223-3dupT		splice_region intron	N/A	NP_001338437.1
	TIA1	NM_001351509.2		c.229-3dupT		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.223-3_223-2insT		splice_region intron	N/A	ENSP00000401371.2
	TIA1	ENST00000415783.6	TSL:1	c.223-3_223-2insT		splice_region intron	N/A	ENSP00000404023.2
	TIA1	ENST00000416149.6	TSL:1	c.223-3_223-2insT		splice_region intron	N/A	ENSP00000413751.2

Frequencies

GnomAD3 genomes AF: 0.000379 AC: 55 AN: 145136 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00151

GnomAD2 exomes AF: 0.0422 AC: 4242 AN: 100452 AF XY: 0.0422

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.0766

Gnomad EAS exome AF: 0.0331

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0533

GnomAD4 exome AF: 0.0462 AC: 39935 AN: 864546 Hom.: 0 Cov.: 30 AF XY: 0.0451 AC XY: 19322 AN XY: 428178

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

African (AFR) AF: 0.0470 AC: 893 AN: 18988

American (AMR) AF: 0.0347 AC: 888 AN: 25582

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 710 AN: 14372

East Asian (EAS) AF: 0.0305 AC: 685 AN: 22456

South Asian (SAS) AF: 0.0503 AC: 2411 AN: 47898

European-Finnish (FIN) AF: 0.0381 AC: 1238 AN: 32500

Middle Eastern (MID) AF: 0.0297 AC: 106 AN: 3574

European-Non Finnish (NFE) AF: 0.0473 AC: 31463 AN: 664560

Other (OTH) AF: 0.0445 AC: 1541 AN: 34616

⚠️ 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: 0.000379 AC: 55 AN: 145184 Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 19 AN XY: 70508

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

African (AFR) AF: 0.000679 AC: 27 AN: 39772

American (AMR) AF: 0.000137 AC: 2 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3382

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5032

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4574

European-Finnish (FIN) AF: 0.00111 AC: 10 AN: 8990

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

European-Non Finnish (NFE) AF: 0.000152 AC: 10 AN: 65680

Other (OTH) AF: 0.00150 AC: 3 AN: 2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000115796), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0519 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=95/5	polymorphism

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: rs750862626; hg19: chr2-70456452; COSMIC: COSV57008942; COSMIC: COSV57008942;