2-70229320-TAAAAA-TAAA

Variant names:

• chr2-70229320-TAA-T
• rs750862626
• NM_022173.4:c.223-4_223-3delTT

Variant summary

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

The NM_022173.4(TIA1):​c.223-4_223-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,078,752 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.341
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.223-4_223-3delTT		splice_region intron	N/A	NP_071505.2	P31483-1
	TIA1	NM_001351508.2		c.223-4_223-3delTT		splice_region intron	N/A	NP_001338437.1	F8W8I6
	TIA1	NM_001351509.2		c.229-4_229-3delTT		splice_region intron	N/A	NP_001338438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	ENST00000433529.7	TSL:2 MANE Select	c.223-4_223-3delTT		splice_region intron	N/A	ENSP00000401371.2	P31483-1
	TIA1	ENST00000415783.6	TSL:1	c.223-4_223-3delTT		splice_region intron	N/A	ENSP00000404023.2	P31483-2
	TIA1	ENST00000416149.6	TSL:1	c.223-4_223-3delTT		splice_region intron	N/A	ENSP00000413751.2	P31483-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 145258 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000796 AC: 8 AN: 100452 AF XY: 0.0000567

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000325

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000306

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 26 AN: 1078752 Hom.: 0 AF XY: 0.0000205 AC XY: 11 AN XY: 536940

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

African (AFR) AF: 0.0000417 AC: 1 AN: 23984

American (AMR) AF: 0.0000649 AC: 2 AN: 30816

Ashkenazi Jewish (ASJ) AF: 0.0000533 AC: 1 AN: 18776

East Asian (EAS) AF: 0.00 AC: 0 AN: 29668

South Asian (SAS) AF: 0.0000646 AC: 4 AN: 61936

European-Finnish (FIN) AF: 0.0000762 AC: 3 AN: 39352

Middle Eastern (MID) AF: 0.000237 AC: 1 AN: 4218

European-Non Finnish (NFE) AF: 0.0000145 AC: 12 AN: 825984

Other (OTH) AF: 0.0000454 AC: 2 AN: 44018

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 145258 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70522

African (AFR) AF: 0.00 AC: 0 AN: 39698

American (AMR) AF: 0.00 AC: 0 AN: 14580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65742

Other (OTH) AF: 0.00 AC: 0 AN: 1990

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 15

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: COSV99248764; COSMIC: COSV99248764;