9-72627898-ATTT-AT

Variant names:

• chr9-72627898-ATT-A
• rs36038786
• NM_138691.3:c.-195-12_-195-11delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_138691.3(TMC1):​c.-195-12_-195-11delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 342,442 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0022 (0 hom.)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0390
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.-195-12_-195-11delTT		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.-195-12_-195-11delTT		intron	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.-195-12_-195-11delTT		intron	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.-195-12_-195-11delTT		intron	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 45 AN: 148758 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000740

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.000205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000597

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00217 AC: 421 AN: 193602 Hom.: 0 AF XY: 0.00236 AC XY: 262 AN XY: 110974

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

African (AFR) AF: 0.00134 AC: 6 AN: 4484

American (AMR) AF: 0.00448 AC: 46 AN: 10258

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 10 AN: 5640

East Asian (EAS) AF: 0.00413 AC: 30 AN: 7260

South Asian (SAS) AF: 0.00309 AC: 123 AN: 39824

European-Finnish (FIN) AF: 0.00318 AC: 26 AN: 8174

Middle Eastern (MID) AF: 0.00127 AC: 2 AN: 1570

European-Non Finnish (NFE) AF: 0.00147 AC: 158 AN: 107326

Other (OTH) AF: 0.00221 AC: 20 AN: 9066

⚠️ 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: 0.000302 AC: 45 AN: 148840 Hom.: 0 Cov.: 24 AF XY: 0.000386 AC XY: 28 AN XY: 72538

African (AFR) AF: 0.0000738 AC: 3 AN: 40658

American (AMR) AF: 0.00201 AC: 30 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.000785 AC: 4 AN: 5094

South Asian (SAS) AF: 0.000425 AC: 2 AN: 4710

European-Finnish (FIN) AF: 0.000205 AC: 2 AN: 9774

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

European-Non Finnish (NFE) AF: 0.0000597 AC: 4 AN: 66970

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00 Hom.: 131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.039

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;