rs376040866

chr9-72700517-GAGA-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM4_Supporting PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_138691.3(TMC1):c.247_249del(p.Glu83del) variant causes a inframe deletion, splice region change. The variant allele was found at a frequency of 0.0119 in 1,588,288 control chromosomes in the GnomAD database, including 157 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (16 hom., cov: 29)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: TMC1 NM_138691.3 inframe_deletion, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.69

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_138691.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-72700517-GAGA-G is Benign according to our data. Variant chr9-72700517-GAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00958 (1451/151504) while in subpopulation NFE AF= 0.0139 (944/67854). AF 95% confidence interval is 0.0132. There are 16 homozygotes in gnomad4. There are 667 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.247_249del	p.Glu83del	inframe_deletion, splice_region_variant	8/24	ENST00000297784.10
TMC1	XM_017014256.2	c.250_252del	p.Glu84del	inframe_deletion, splice_region_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.247_249del	p.Glu83del	inframe_deletion, splice_region_variant	8/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1454 AN: 151392 Hom.: 16 Cov.: 29

Gnomad AFR AF: 0.00245

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00646

Gnomad FIN AF: 0.00475

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0173

GnomAD3 exomes AF: 0.0100 AC: 2464 AN: 245610 Hom.: 21 AF XY: 0.0107 AC XY: 1422 AN XY: 132872

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.00789

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00468

Gnomad FIN exome AF: 0.00534

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0122 AC: 17463 AN: 1436784 Hom.: 141 AF XY: 0.0122 AC XY: 8701 AN XY: 715396

Gnomad4 AFR exome AF: 0.00282

Gnomad4 AMR exome AF: 0.00827

Gnomad4 ASJ exome AF: 0.00747

Gnomad4 EAS exome AF: 0.0000774

Gnomad4 SAS exome AF: 0.00416

Gnomad4 FIN exome AF: 0.00585

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00958 AC: 1451 AN: 151504 Hom.: 16 Cov.: 29 AF XY: 0.00901 AC XY: 667 AN XY: 74050

Gnomad4 AFR AF: 0.00244

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00646

Gnomad4 FIN AF: 0.00475

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0120 Hom.: 6

Bravo AF: 0.0103

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 08, 2011	Glu83del in exon 8 of TMC1: This variant is not expected to have clinical signif icance because it has been found in 5/114 or 4.39% of White individuals, none of whom had a variant on the other allele and two cases had other clear etiologies for hearing loss. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2018	This variant is associated with the following publications: (PMID: 26969326) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TMC1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Nonsyndromic Hearing Loss, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nonsyndromic Hearing Loss, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 4
DS_AL_spliceai		0.96		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376040866; hg19: chr9-75315433;