9-72792243-T-G

Variant names:

• chr9-72792243-T-G
• NM_138691.3:c.1457T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138691.3(TMC1):​c.1457T>G​(p.Met486Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M486T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25266597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1457T>G	p.Met486Arg	missense_variant	Exon 17 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1460T>G	p.Met487Arg	missense_variant	Exon 14 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1457T>G	p.Met486Arg	missense_variant	Exon 17 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;T;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;.;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;L;.;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;.;.;N;.
REVEL	Benign	0.18
Sift	Benign	0.12	T;.;.;T;.
Sift4G	Benign	0.10	T;.;.;T;.
Polyphen		0.091	B;B;.;B;.
Vest4		0.51
MutPred		0.50		Loss of catalytic residue at M486 (P = 0.0302);Loss of catalytic residue at M486 (P = 0.0302);.;Loss of catalytic residue at M486 (P = 0.0302);.;
MVP		0.83
MPC		0.26
ClinPred		0.51	D
GERP RS		6.0
Varity_R		0.55
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-75407159;