2-70229321-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022173.4(TIA1):​c.223-3T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 680,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TIA1 NM_022173.4 splice_region, intron
• Scores: Splicing: ADA: 0.002522
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BS2: High AC in GnomAdExome4 at 27 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.223-3T>A		splice_region intron	N/A	NP_071505.2	P31483-1
	TIA1	NM_001351508.2		c.223-3T>A		splice_region intron	N/A	NP_001338437.1	F8W8I6
	TIA1	NM_001351509.2		c.229-3T>A		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>A		splice_region intron	N/A	ENSP00000401371.2	P31483-1
	TIA1	ENST00000415783.6	TSL:1	c.223-3T>A		splice_region intron	N/A	ENSP00000404023.2	P31483-2
	TIA1	ENST00000416149.6	TSL:1	c.223-3T>A		splice_region intron	N/A	ENSP00000413751.2	P31483-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000353 AC: 4 AN: 113318 AF XY: 0.0000166

Gnomad AFR exome AF: 0.000113

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: 0.0000365

Gnomad OTH exome AF: 0.000387

GnomAD4 exome AF: 0.0000397 AC: 27 AN: 680304 Hom.: 0 Cov.: 30 AF XY: 0.0000355 AC XY: 12 AN XY: 337742

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

American (AMR) AF: 0.0000519 AC: 1 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: 0.00109 AC: 3 AN: 2762

European-Non Finnish (NFE) AF: 0.0000344 AC: 18 AN: 522814

Other (OTH) AF: 0.000183 AC: 5 AN: 27272

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.50
PhyloP100		-1.6
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -7

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

Other links and lift over

dbSNP: rs750261656; hg19: chr2-70456453;