rs61753709

Positions:

• chr8-72050805-C-T

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.1878G>A​(p.Met626Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00367 in 1,611,682 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (23 hom.)
• Consequence: TRPA1 NM_007332.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.18

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=0.011384249).
• BP6: Variant 8-72050805-C-T is Benign according to our data. Variant chr8-72050805-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 341 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPA1	NM_007332.3	c.1878G>A	p.Met626Ile	missense_variant	15/27	ENST00000262209.5
MSC-AS1	NR_033652.1	n.1029-1734C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPA1	ENST00000262209.5	c.1878G>A	p.Met626Ile	missense_variant	15/27	1	NM_007332.3	P1
MSC-AS1	ENST00000518916.5	n.392-1734C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152138 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00195 AC: 489 AN: 250316 Hom.: 2 AF XY: 0.00193 AC XY: 261 AN XY: 135308

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00382 AC: 5579 AN: 1459426 Hom.: 23 Cov.: 30 AF XY: 0.00363 AC XY: 2633 AN XY: 726184

Gnomad4 AFR exome AF: 0.000868

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152256 Hom.: 3 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74448

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00407

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00343 Hom.: 2

Bravo AF: 0.00226

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00396 AC: 34

ExAC AF: 0.00181 AC: 220

EpiCase AF: 0.00420

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TRPA1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.11
Sift	Benign	0.071	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.36	.;B
Vest4		0.52
MutPred		0.45		.;Loss of catalytic residue at M626 (P = 0.0048);
MVP		0.47
MPC		0.13
ClinPred		0.023	T
GERP RS		5.0
Varity_R		0.54
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61753709; hg19: chr8-72963040;