chr19-3595925-G-A

Variant names:

• chr19-3595925-G-A
• rs1131882
• ENST00000589966.1:c.406C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000589966.1(TBXA2R):​c.406C>T​(p.Arg136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,590,290 control chromosomes in the GnomAD database, including 29,341 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2815 hom., cov: 32)
  • Exomes 𝑓: 0.17 (26526 hom.)
• Consequence: TBXA2R ENST00000589966.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.249
• Publications: 63 publications found

Genes affected

TBXA2R (HGNC:11608): (thromboxane A2 receptor) This gene encodes a member of the G protein-coupled receptor family. The protein interacts with thromboxane A2 to induce platelet aggregation and regulate hemostasis. A mutation in this gene results in a bleeding disorder. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

TBXA2R Gene-Disease associations (from GenCC):

• qualitative platelet defect

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• bleeding diathesis due to thromboxane synthesis deficiency

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3116118E-5).
• BP6: Variant 19-3595925-G-A is Benign according to our data. Variant chr19-3595925-G-A is described in ClinVar as Benign. ClinVar VariationId is 263268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXA2R	NM_001060.6	c.795C>T	p.Ile265Ile	synonymous_variant	Exon 3 of 3	ENST00000375190.10	NP_001051.1
TBXA2R	NM_201636.3	c.795C>T	p.Ile265Ile	synonymous_variant	Exon 3 of 4		NP_963998.2
TBXA2R	XM_011528214.3	c.795C>T	p.Ile265Ile	synonymous_variant	Exon 4 of 4		XP_011526516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBXA2R	ENST00000589966.1	c.406C>T	p.Arg136Cys	missense_variant	Exon 2 of 2	1		ENSP00000468145.1
TBXA2R	ENST00000375190.10	c.795C>T	p.Ile265Ile	synonymous_variant	Exon 3 of 3	1	NM_001060.6	ENSP00000364336.4
TBXA2R	ENST00000411851.3	c.795C>T	p.Ile265Ile	synonymous_variant	Exon 3 of 4	2		ENSP00000393333.2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23706 AN: 152060 Hom.: 2809 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.223 AC: 45836 AN: 205122 AF XY: 0.216

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.170 AC: 244978 AN: 1438112 Hom.: 26526 Cov.: 41 AF XY: 0.171 AC XY: 122204 AN XY: 713250

African (AFR) AF: 0.0522 AC: 1731 AN: 33170

American (AMR) AF: 0.359 AC: 14685 AN: 40910

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6306 AN: 25578

East Asian (EAS) AF: 0.625 AC: 24046 AN: 38488

South Asian (SAS) AF: 0.187 AC: 15526 AN: 82970

European-Finnish (FIN) AF: 0.147 AC: 7409 AN: 50394

Middle Eastern (MID) AF: 0.207 AC: 1107 AN: 5340

European-Non Finnish (NFE) AF: 0.148 AC: 163110 AN: 1101858

Other (OTH) AF: 0.186 AC: 11058 AN: 59404

GnomAD4 genome AF: 0.156 AC: 23712 AN: 152178 Hom.: 2815 Cov.: 32 AF XY: 0.160 AC XY: 11904 AN XY: 74404

African (AFR) AF: 0.0590 AC: 2452 AN: 41550

American (AMR) AF: 0.250 AC: 3831 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 860 AN: 3472

East Asian (EAS) AF: 0.607 AC: 3128 AN: 5152

South Asian (SAS) AF: 0.200 AC: 965 AN: 4818

European-Finnish (FIN) AF: 0.148 AC: 1570 AN: 10610

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.151 AC: 10238 AN: 67964

Other (OTH) AF: 0.166 AC: 349 AN: 2108

Alfa AF: 0.161 Hom.: 5329

Bravo AF: 0.166

TwinsUK AF: 0.142 AC: 526

ALSPAC AF: 0.153 AC: 588

ESP6500AA AF: 0.0552 AC: 226

ESP6500EA AF: 0.153 AC: 1276

ExAC AF: 0.192 AC: 22779

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11922633, 23517037) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.4
DANN	Benign	0.87
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.000013	T
PhyloP100		0.25
Sift4G	Benign	0.087	T
Vest4		0.20
GERP RS		-0.79
Mutation Taster		=61/39	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1131882; hg19: chr19-3595923; COSMIC: COSV59260740; COSMIC: COSV59260740;