8-72023910-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007332.3(TRPA1):c.3053A>G(p.His1018Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,557,990 control chromosomes in the GnomAD database, including 24,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1921 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22986 hom.)
• Consequence: TRPA1 NM_007332.3 missense, splice_region
• Scores: Splicing: ADA: 0.00001829
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.421

Genes affected

TRPA1 (HGNC:497): (transient receptor potential cation channel subfamily A member 1) The structure of the protein encoded by this gene is highly related to both the protein ankyrin and transmembrane proteins. The specific function of this protein has not yet been determined; however, studies indicate the function may involve a role in signal transduction and growth control. [provided by RefSeq, Jul 2008]

MSC-AS1 (HGNC:48724): (MSC antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057715178).
• BP6: Variant 8-72023910-T-C is Benign according to our data. Variant chr8-72023910-T-C is described in ClinVar as [Benign]. Clinvar id is 1342276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPA1	NM_007332.3	c.3053A>G	p.His1018Arg	missense_variant, splice_region_variant	26/27	ENST00000262209.5
MSC-AS1	NR_033652.1	n.1029-28629T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPA1	ENST00000262209.5	c.3053A>G	p.His1018Arg	missense_variant, splice_region_variant	26/27	1	NM_007332.3	P1
MSC-AS1	ENST00000518916.5	n.392-28629T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21186 AN: 152130 Hom.: 1922 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.179 AC: 44592 AN: 249376 Hom.: 4895 AF XY: 0.188 AC XY: 25409 AN XY: 134842

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.0854

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.366

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.172 AC: 241151 AN: 1405742 Hom.: 22986 Cov.: 25 AF XY: 0.176 AC XY: 123703 AN XY: 702296

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0874

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.378

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.139 AC: 21187 AN: 152248 Hom.: 1921 Cov.: 33 AF XY: 0.141 AC XY: 10478 AN XY: 74462

Gnomad4 AFR AF: 0.0434

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.163

Alfa AF: 0.177 Hom.: 6235

Bravo AF: 0.131

TwinsUK AF: 0.165 AC: 610

ALSPAC AF: 0.160 AC: 616

ESP6500AA AF: 0.0508 AC: 223

ESP6500EA AF: 0.178 AC: 1524

ExAC AF: 0.180 AC: 21880

Asia WGS AF: 0.240 AC: 833 AN: 3476

EpiCase AF: 0.175

EpiControl AF: 0.183

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TRPA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial episodic pain syndrome with predominantly upper body involvement Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.54
Dann	Benign	0.41
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00099	N
LIST_S2	Benign	0.22	T;T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.031
Sift	Benign	0.56	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	.;B
Vest4		0.012
MPC		0.12
ClinPred		0.0062	T
GERP RS		0.88
Varity_R		0.036
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0060
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

Publications

LitVar

Other links and lift over

dbSNP: rs959976; hg19: chr8-72936145; COSMIC: COSV51558544; COSMIC: COSV51558544;