2-70229320-TAAAAA-TA

Variant names:

• chr2-70229320-TAAAA-T
• rs750862626
• NM_022173.4:c.223-6_223-3delTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022173.4(TIA1):​c.223-6_223-3delTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000653 in 1,225,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.28
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD,Unknown,SD gene.

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.223-6_223-3delTTTT		splice_region intron	N/A	NP_071505.2	P31483-1
	TIA1	NM_001351508.2		c.223-6_223-3delTTTT		splice_region intron	N/A	NP_001338437.1	F8W8I6
	TIA1	NM_001351509.2		c.229-6_229-3delTTTT		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.223-6_223-3delTTTT		splice_region intron	N/A	ENSP00000401371.2	P31483-1
	TIA1	ENST00000415783.6	TSL:1	c.223-6_223-3delTTTT		splice_region intron	N/A	ENSP00000404023.2	P31483-2
	TIA1	ENST00000416149.6	TSL:1	c.223-6_223-3delTTTT		splice_region intron	N/A	ENSP00000413751.2	P31483-3

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 145266 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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000555 AC: 6 AN: 1080596 Hom.: 0 AF XY: 0.00000186 AC XY: 1 AN XY: 537772

African (AFR) AF: 0.00 AC: 0 AN: 24018

American (AMR) AF: 0.00 AC: 0 AN: 30866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18798

East Asian (EAS) AF: 0.00 AC: 0 AN: 29690

South Asian (SAS) AF: 0.00 AC: 0 AN: 62028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4224

European-Non Finnish (NFE) AF: 0.00000725 AC: 6 AN: 827458

Other (OTH) AF: 0.00 AC: 0 AN: 44090

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 145266 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70524

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

African (AFR) AF: 0.00 AC: 0 AN: 39700

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: 9040

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

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65742

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Welander distal myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs750862626; hg19: chr2-70456452;