2-70212794-C-T

Variant names:

• chr2-70212794-C-T
• rs72902461
• NM_022173.4:c.1086G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022173.4(TIA1):​c.1086G>A​(p.Pro362Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,056 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (6 hom.)
• Consequence: TIA1 NM_022173.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.07
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-70212794-C-T is Benign according to our data. Variant chr2-70212794-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 448688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00615 (937/152282) while in subpopulation AFR AF = 0.0217 (900/41566). AF 95% confidence interval is 0.0205. There are 11 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 937 AD,Unknown 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	NM_022173.4	MANE Select	c.1086G>A	p.Pro362Pro	synonymous	Exon 13 of 13	NP_071505.2
	TIA1	NM_001351508.2		c.1083G>A	p.Pro361Pro	synonymous	Exon 13 of 13	NP_001338437.1
	TIA1	NM_001351509.2		c.1059G>A	p.Pro353Pro	synonymous	Exon 12 of 12	NP_001338438.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	ENST00000433529.7	TSL:2 MANE Select	c.1086G>A	p.Pro362Pro	synonymous	Exon 13 of 13	ENSP00000401371.2
	TIA1	ENST00000415783.6	TSL:1	c.1053G>A	p.Pro351Pro	synonymous	Exon 12 of 12	ENSP00000404023.2
	TIA1	ENST00000881363.1		c.1182G>A	p.Pro394Pro	synonymous	Exon 14 of 14	ENSP00000551422.1

Frequencies

GnomAD3 genomes AF: 0.00616 AC: 938 AN: 152164 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00156 AC: 393 AN: 251448 AF XY: 0.00109

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000609 AC: 890 AN: 1461774 Hom.: 6 Cov.: 30 AF XY: 0.000505 AC XY: 367 AN XY: 727210

African (AFR) AF: 0.0229 AC: 767 AN: 33478

American (AMR) AF: 0.00107 AC: 48 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111932

Other (OTH) AF: 0.000994 AC: 60 AN: 60390

GnomAD4 genome AF: 0.00615 AC: 937 AN: 152282 Hom.: 11 Cov.: 32 AF XY: 0.00592 AC XY: 441 AN XY: 74460

African (AFR) AF: 0.0217 AC: 900 AN: 41566

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00676

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Welander distal myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.091
DANN	Benign	0.75
PhyloP100		-2.1
Mutation Taster		=99/1	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: rs72902461; hg19: chr2-70439926;