8-72026025-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007332.3(TRPA1):c.2986C>T(p.Arg996Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: TRPA1 NM_007332.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.48

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012704015).
• BP6: Variant 8-72026025-G-A is Benign according to our data. Variant chr8-72026025-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1711678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPA1	NM_007332.3	c.2986C>T	p.Arg996Cys	missense_variant	25/27	ENST00000262209.5
MSC-AS1	NR_033652.1	n.1029-26514G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPA1	ENST00000262209.5	c.2986C>T	p.Arg996Cys	missense_variant	25/27	1	NM_007332.3	P1
MSC-AS1	ENST00000518916.5	n.392-26514G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251308 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135820

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461672 Hom.: 1 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727150

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74496

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000441 Hom.: 0

Bravo AF: 0.00107

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

TRPA1: BS1, BS2 -

TRPA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2021

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.15
Sift	Benign	0.045	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	.;D
Vest4		0.38
MVP		0.74
MPC		0.38
ClinPred		0.081	T
GERP RS		2.7
Varity_R		0.17
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs61758121; hg19: chr8-72938260; COSMIC: COSV51575744; COSMIC: COSV51575744;