chr9-72684468-G-A

Variant names:

• chr9-72684468-G-A
• rs2589619
• NM_138691.3:c.17-4241G>A

Variant summary

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

The NM_138691.3(TMC1):​c.17-4241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,936 control chromosomes in the GnomAD database, including 25,117 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 0.56 (25117 hom., cov: 31)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.653
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.17-4241G>A		intron_variant	Intron 5 of 23	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.20-4241G>A		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.17-4241G>A		intron_variant	Intron 5 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84875 AN: 151818 Hom.: 25071 Cov.: 31

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.559 AC: 84977 AN: 151936 Hom.: 25117 Cov.: 31 AF XY: 0.555 AC XY: 41219 AN XY: 74230

African (AFR) AF: 0.767 AC: 31814 AN: 41464

American (AMR) AF: 0.509 AC: 7758 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3470

East Asian (EAS) AF: 0.454 AC: 2337 AN: 5142

South Asian (SAS) AF: 0.466 AC: 2244 AN: 4820

European-Finnish (FIN) AF: 0.453 AC: 4777 AN: 10546

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32384 AN: 67930

Other (OTH) AF: 0.560 AC: 1179 AN: 2106

Alfa AF: 0.471 Hom.: 8323

Bravo AF: 0.576

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.52
DANN	Benign	0.52
PhyloP100		-0.65
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: rs2589619; hg19: chr9-75299384; COSMIC: COSV52771071;