NM_138691.3:c.363-14796A>G

Variant names:

• chr9-72725323-A-G
• rs1630623
• NM_138691.3:c.363-14796A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138691.3(TMC1):​c.363-14796A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.30 (4394 hom., cov: 18)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.363-14796A>G		intron_variant	Intron 8 of 23	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.366-14796A>G		intron_variant	Intron 5 of 20		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.363-14796A>G		intron_variant	Intron 8 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.295 AC: 31388 AN: 106252 Hom.: 4390 Cov.: 18

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.291

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

GnomAD4 genome AF: 0.295 AC: 31391 AN: 106232 Hom.: 4394 Cov.: 18 AF XY: 0.307 AC XY: 15344 AN XY: 49986

African (AFR) AF: 0.394 AC: 10664 AN: 27080

American (AMR) AF: 0.356 AC: 3655 AN: 10280

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 999 AN: 2960

East Asian (EAS) AF: 0.455 AC: 1825 AN: 4008

South Asian (SAS) AF: 0.402 AC: 1417 AN: 3528

European-Finnish (FIN) AF: 0.331 AC: 1410 AN: 4262

Middle Eastern (MID) AF: 0.284 AC: 58 AN: 204

European-Non Finnish (NFE) AF: 0.208 AC: 10814 AN: 51900

Other (OTH) AF: 0.295 AC: 416 AN: 1410

Alfa AF: 0.214 Hom.: 399

Bravo AF: 0.230

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.73
DANN	Benign	0.34
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1630623; hg19: chr9-75340239;