9-72792030-T-G

Position:

• chr9-72792030-T-G

Variant summary

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

The NM_138691.3(TMC1):​c.1369T>G​(p.Phe457Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F457L) has been classified as Uncertain significance.

• 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: 7.96

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 transmembrane_region Helical (size 20) in uniprot entity TMC1_HUMAN there are 5 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, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.1369T>G	p.Phe457Val	missense_variant	16/24	ENST00000297784.10
TMC1	XM_017014256.2	c.1372T>G	p.Phe458Val	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.1369T>G	p.Phe457Val	missense_variant	16/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D;.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D;.;.;D;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	D;.;.;D;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		0.97	D;D;.;D;.
Vest4		0.86
MVP		0.81
MPC		0.50
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517836; hg19: chr9-75406946;