9-72627898-ATTT-ATTTT

Variant names:

• chr9-72627898-A-AT
• rs36038786
• NM_138691.3:c.-195-11dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_138691.3(TMC1):​c.-195-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 336,760 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 24)
  • Exomes 𝑓: 0.030 (0 hom.)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• 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):

• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00257 (382/148784) while in subpopulation AFR AF = 0.00477 (194/40648). AF 95% confidence interval is 0.00422. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

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.-195-11dupT		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.-195-11dupT		intron	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.-195-11dupT		intron	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.-195-11dupT		intron	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 377 AN: 148704 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00469

Gnomad AMI AF: 0.0256

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00318

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00148

GnomAD4 exome AF: 0.0297 AC: 5579 AN: 187976 Hom.: 0 Cov.: 0 AF XY: 0.0292 AC XY: 3151 AN XY: 107934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0301 AC: 130 AN: 4324

American (AMR) AF: 0.0262 AC: 261 AN: 9964

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 158 AN: 5550

East Asian (EAS) AF: 0.0208 AC: 148 AN: 7108

South Asian (SAS) AF: 0.0254 AC: 990 AN: 39038

European-Finnish (FIN) AF: 0.0282 AC: 224 AN: 7956

Middle Eastern (MID) AF: 0.0129 AC: 20 AN: 1552

European-Non Finnish (NFE) AF: 0.0326 AC: 3378 AN: 103678

Other (OTH) AF: 0.0307 AC: 270 AN: 8806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00257 AC: 382 AN: 148784 Hom.: 1 Cov.: 24 AF XY: 0.00247 AC XY: 179 AN XY: 72502

African (AFR) AF: 0.00477 AC: 194 AN: 40648

American (AMR) AF: 0.000669 AC: 10 AN: 14956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00318 AC: 15 AN: 4710

European-Finnish (FIN) AF: 0.00164 AC: 16 AN: 9762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00179 AC: 120 AN: 66942

Other (OTH) AF: 0.00195 AC: 4 AN: 2048

Alfa AF: 0.000358 Hom.: 131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.042
Mutation Taster		=100/0	polymorphism

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: rs36038786; hg19: chr9-75242814;