9-72671401-A-T

Variant names:

• chr9-72671401-A-T
• rs1417619
• NM_138691.3:c.17-17308A>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.17-17308A>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 152,114 control chromosomes in the GnomAD database, including 4,762 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 (4762 hom., cov: 32)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• Publications: 0 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 = 0.37 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	NM_138691.3	MANE Select	c.17-17308A>T		intron	N/A	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.17-17308A>T		intron	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.17-17308A>T		intron	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.17-17308A>T		intron	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36625 AN: 151996 Hom.: 4749 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.215

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: 36663 AN: 152114 Hom.: 4762 Cov.: 32 AF XY: 0.245 AC XY: 18226 AN XY: 74342

African (AFR) AF: 0.303 AC: 12570 AN: 41490

American (AMR) AF: 0.278 AC: 4242 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1025 AN: 3472

East Asian (EAS) AF: 0.384 AC: 1984 AN: 5166

South Asian (SAS) AF: 0.328 AC: 1581 AN: 4818

European-Finnish (FIN) AF: 0.228 AC: 2413 AN: 10568

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

European-Non Finnish (NFE) AF: 0.179 AC: 12154 AN: 68010

Other (OTH) AF: 0.234 AC: 494 AN: 2110

Alfa AF: 0.118 Hom.: 191

Bravo AF: 0.245

Asia WGS AF: 0.351 AC: 1217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.1
DANN	Benign	0.79
PhyloP100		0.67
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: rs1417619; hg19: chr9-75286317;