9-72650143-C-T

Variant names:

• chr9-72650143-C-T
• rs12553768
• NM_138691.3:c.16+1479C>T

Variant summary

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

The NM_138691.3(TMC1):​c.16+1479C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,018 control chromosomes in the GnomAD database, including 4,758 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 0.24 (4758 hom., cov: 32)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.978
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.16+1479C>T		intron_variant	Intron 5 of 23	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.19+33666C>T		intron_variant	Intron 2 of 20		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.16+1479C>T		intron_variant	Intron 5 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36618 AN: 151898 Hom.: 4745 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.241 AC: 36656 AN: 152018 Hom.: 4758 Cov.: 32 AF XY: 0.245 AC XY: 18225 AN XY: 74296

African (AFR) AF: 0.303 AC: 12569 AN: 41464

American (AMR) AF: 0.277 AC: 4232 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1024 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1981 AN: 5176

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4816

European-Finnish (FIN) AF: 0.230 AC: 2425 AN: 10554

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12148 AN: 67966

Other (OTH) AF: 0.234 AC: 494 AN: 2114

Alfa AF: 0.111 Hom.: 173

Bravo AF: 0.245

Asia WGS AF: 0.350 AC: 1214 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.33
PhyloP100		-0.98
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: rs12553768; hg19: chr9-75265059;