rs750261656

Variant names:

• chr2-70229321-A-G
• rs750261656
• NM_022173.4:c.223-3T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-70229321-A-G
• chr2-70229321-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022173.4(TIA1):​c.223-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 826,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001469
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

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

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146522 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000249

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: 0.00 AC: 0 AN: 113318 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000294 AC: 2 AN: 680304 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 337742

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

African (AFR) AF: 0.00 AC: 0 AN: 15290

American (AMR) AF: 0.00 AC: 0 AN: 19278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10962

East Asian (EAS) AF: 0.00 AC: 0 AN: 19114

South Asian (SAS) AF: 0.00 AC: 0 AN: 37730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2762

European-Non Finnish (NFE) AF: 0.00000383 AC: 2 AN: 522814

Other (OTH) AF: 0.00 AC: 0 AN: 27272

⚠️ 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: 0.00000682 AC: 1 AN: 146522 Hom.: 0 Cov.: 30 AF XY: 0.0000140 AC XY: 1 AN XY: 71318

African (AFR) AF: 0.0000249 AC: 1 AN: 40174

American (AMR) AF: 0.00 AC: 0 AN: 14634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9298

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66080

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.2
DANN	Benign	0.60
PhyloP100		-1.6
PromoterAI		0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.010		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: rs750261656; hg19: chr2-70456453;