rs397517841

Variant names:

• chr9-72740159-G-A
• rs397517841
• NM_138691.3:c.403G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138691.3(TMC1):​c.403G>A​(p.Gly135Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.403G>A	p.Gly135Arg	missense_variant	Exon 9 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.406G>A	p.Gly136Arg	missense_variant	Exon 6 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.403G>A	p.Gly135Arg	missense_variant	Exon 9 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251388 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Gly135Arg varia nt in TMC1 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across mammals and birds and computati onal analyses (PolyPhen2, SIFT) suggest that the Gly135Arg variant may impact th e protein. However, this information is not predictive enough to assume pathogen icity. In summary, the clinical significance of this variant cannot be determine d with certainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;D;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.1	M;M;.;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D;.;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;.;.;D
Sift4G	Uncertain	0.015	D;.;.;D
Polyphen		1.0	D;D;.;D
Vest4		0.51
MutPred		0.31		Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);.;Gain of MoRF binding (P = 0.0199);
MVP		0.76
MPC		0.76
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.56
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397517841; hg19: chr9-75355075;