rs868082421

Positions:

• 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 ENST00000297784.10(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 ENST00000297784.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000297784.10
• 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/exons	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1265C>A	p.Thr422Lys	missense_variant	16/24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1268C>A	p.Thr423Lys	missense_variant	13/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1265C>A	p.Thr422Lys	missense_variant	16/24	1	NM_138691.3	ENSP00000297784	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2016

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. -

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;.
MutationTaster	Benign	0.99	D;D;D
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;