2-70214405-A-G

Variant names:

• chr2-70214405-A-G
• rs78236170
• NM_022173.4:c.978T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_022173.4(TIA1):​c.978T>C​(p.Gly326Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000555 in 1,614,010 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G326G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: TIA1 NM_022173.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-70214405-A-G is Benign according to our data. Variant chr2-70214405-A-G is described in ClinVar as Benign. ClinVar VariationId is 458844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BS2: High AC in GnomAd4 at 450 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	NM_022173.4	MANE Select	c.978T>C	p.Gly326Gly	synonymous	Exon 12 of 13	NP_071505.2	P31483-1
	TIA1	NM_001351508.2		c.975T>C	p.Gly325Gly	synonymous	Exon 12 of 13	NP_001338437.1	F8W8I6
	TIA1	NM_001351509.2		c.951T>C	p.Gly317Gly	synonymous	Exon 11 of 12	NP_001338438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIA1	ENST00000433529.7	TSL:2 MANE Select	c.978T>C	p.Gly326Gly	synonymous	Exon 12 of 13	ENSP00000401371.2	P31483-1
	TIA1	ENST00000415783.6	TSL:1	c.945T>C	p.Gly315Gly	synonymous	Exon 11 of 12	ENSP00000404023.2	P31483-2
	TIA1	ENST00000881363.1		c.1074T>C	p.Gly358Gly	synonymous	Exon 13 of 14	ENSP00000551422.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000756 AC: 190 AN: 251296 AF XY: 0.000552

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000305 AC: 446 AN: 1461690 Hom.: 3 Cov.: 31 AF XY: 0.000274 AC XY: 199 AN XY: 727150

African (AFR) AF: 0.0107 AC: 358 AN: 33458

American (AMR) AF: 0.000492 AC: 22 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5754

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111954

Other (OTH) AF: 0.000878 AC: 53 AN: 60384

GnomAD4 genome AF: 0.00295 AC: 450 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74484

African (AFR) AF: 0.0103 AC: 427 AN: 41578

American (AMR) AF: 0.00105 AC: 16 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.37
CADD	Benign	6.6
DANN	Benign	0.79
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs78236170; hg19: chr2-70441537;