9-72695225-T-C

Variant names:

• chr9-72695225-T-C
• rs1444829
• NM_138691.3:c.236+511T>C

Variant summary

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

The NM_138691.3(TMC1):​c.236+511T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 151,992 control chromosomes in the GnomAD database, including 25,655 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 0.57 (25655 hom., cov: 31)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• 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 (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.236+511T>C		intron_variant	Intron 7 of 23	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.239+511T>C		intron_variant	Intron 4 of 20		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.236+511T>C		intron_variant	Intron 7 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85848 AN: 151874 Hom.: 25610 Cov.: 31

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.565 AC: 85948 AN: 151992 Hom.: 25655 Cov.: 31 AF XY: 0.562 AC XY: 41741 AN XY: 74292

African (AFR) AF: 0.773 AC: 32076 AN: 41472

American (AMR) AF: 0.513 AC: 7817 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1891 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2329 AN: 5166

South Asian (SAS) AF: 0.467 AC: 2250 AN: 4818

European-Finnish (FIN) AF: 0.460 AC: 4855 AN: 10562

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32892 AN: 67944

Other (OTH) AF: 0.566 AC: 1195 AN: 2110

Alfa AF: 0.532 Hom.: 2768

Bravo AF: 0.581

Asia WGS AF: 0.481 AC: 1670 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.6
DANN	Benign	0.68
PhyloP100		-1.8
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: rs1444829; hg19: chr9-75310141; COSMIC: COSV52771178;