rs868082421

Variant names:

• chr9-72791926-C-A
• rs868082421
• NM_138691.3:c.1265C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-72791926-C-A
• chr9-72791926-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_138691.3(TMC1):​c.1265C>A​(p.Thr422Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.81

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 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 53) in uniprot entity TMC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_138691.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35909525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1265C>A	p.Thr422Lys	missense_variant	Exon 16 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1268C>A	p.Thr423Lys	missense_variant	Exon 13 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1265C>A	p.Thr422Lys	missense_variant	Exon 16 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2016

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 Pathogenic. The p.Thr422Lys variant in TMC1 has been identified by our laboratory in 1 individual with hear ing loss and segregated in 2 affected family members. This variant has not been identified in large population studies. Computational prediction tools and cons ervation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the cl inical significance of this variant is uncertain. -

not provided Uncertain:1

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 422 of the TMC1 protein (p.Thr422Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 33824189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMC1 protein function. Experimental studies have shown that this missense change affects TMC1 function (PMID: 33824189). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;T;.;T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L;L;.;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;.;.;N;.
REVEL	Benign	0.26
Sift	Benign	0.23	T;.;.;T;.
Sift4G	Uncertain	0.0080	D;.;.;D;.
Polyphen		0.042	B;B;.;B;.
Vest4		0.77
MutPred		0.43		Gain of ubiquitination at T422 (P = 0.0247);Gain of ubiquitination at T422 (P = 0.0247);.;Gain of ubiquitination at T422 (P = 0.0247);.;
MVP		0.59
MPC		0.23
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.38
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs868082421; hg19: chr9-75406842;