rs397517837

Positions:

• chr9-72821066-A-G
• chr9-72821066-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_138691.3(TMC1):​c.1988A>G​(p.Asp663Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D663D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 5 ACMG points.

• PM1: In a topological_domain Extracellular (size 43) in uniprot entity TMC1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_138691.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.1988A>G	p.Asp663Gly	missense_variant	20/24	ENST00000297784.10
TMC1	XM_017014256.2	c.1991A>G	p.Asp664Gly	missense_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.1988A>G	p.Asp663Gly	missense_variant	20/24	1	NM_138691.3	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 20, 2011

Variant classified as Uncertain Significance - Favor Benign. The Asp663Gly varia nt in TMC1 has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, homo logy, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against p athogenicity. In summary, the clinical significance of this variant cannot be d etermined with certainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;.;.;D;.
REVEL	Uncertain	0.50
Sift	Benign	0.061	T;.;.;T;.
Sift4G	Uncertain	0.0060	D;.;.;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.86
MutPred		0.29		Loss of solvent accessibility (P = 0.0477);Loss of solvent accessibility (P = 0.0477);.;Loss of solvent accessibility (P = 0.0477);.;
MVP		0.85
MPC		0.80
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.83

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: rs397517837; hg19: chr9-75435982;