rs2278669

chr9-72597302-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138691.3(TMC1):c.-305-19066A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,086 control chromosomes in the GnomAD database, including 18,529 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18529 hom., cov: 33)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.-305-19066A>G		intron_variant		ENST00000297784.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.-305-19066A>G		intron_variant		1	NM_138691.3	P2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74619 AN: 151968 Hom.: 18512 Cov.: 33

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 74688 AN: 152086 Hom.: 18529 Cov.: 33 AF XY: 0.490 AC XY: 36420 AN XY: 74328

Gnomad4 AFR AF: 0.566

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.482

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.493

Alfa AF: 0.487 Hom.: 2228

Bravo AF: 0.496

Asia WGS AF: 0.446 AC: 1549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.0090
Dann	Benign	0.27

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: rs2278669; hg19: chr9-75212218; COSMIC: COSV52770467;