9-72820980-C-G

Variant names:

• chr9-72820980-C-G
• rs767285617
• NM_138691.3:c.1902C>G

Variant summary

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

The NM_138691.3(TMC1):​c.1902C>G​(p.Asn634Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.112

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.1902C>G	p.Asn634Lys	missense_variant	Exon 20 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1905C>G	p.Asn635Lys	missense_variant	Exon 17 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1902C>G	p.Asn634Lys	missense_variant	Exon 20 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251422 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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 AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn634Lys variant in TMC1 has not been previously reported in individuals with hearing loss or in large population studies. Asparagine (Asn) at position 6 34 is not conserved in mammals and 1 mammal (Pacific walrus) carries a lysine (L ys), raising the possibility that this change may be tolerated. Additional comp utational prediction tools do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the p.Asn634Lys varia nt is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;D;.;D;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	.;.;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D;.;.;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.83	P;P;.;P;.
Vest4		0.78
MutPred		0.55		Loss of catalytic residue at N634 (P = 0.0215);Loss of catalytic residue at N634 (P = 0.0215);.;Loss of catalytic residue at N634 (P = 0.0215);.;
MVP		0.74
MPC		0.55
ClinPred		1.0	D
GERP RS		-6.1
Varity_R		0.97
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs767285617; hg19: chr9-75435896;