chr9-72821066-A-T

Position:

• chr9-72821066-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138691.3(TMC1):​c.1988A>T​(p.Asp663Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

TMC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1988A>T	p.Asp663Val	missense_variant	20/24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1991A>T	p.Asp664Val	missense_variant	17/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1988A>T	p.Asp663Val	missense_variant	20/24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.4	D;.;.;D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.91
MutPred		0.40		Loss of disorder (P = 0.0406);Loss of disorder (P = 0.0406);.;Loss of disorder (P = 0.0406);.;
MVP		0.90
MPC		0.84
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;