rs34532421

Variant names:

• chr9-72816160-C-T
• rs34532421
• NM_138691.3:c.1713C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_138691.3(TMC1):​c.1713C>T​(p.Phe571Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,570 control chromosomes in the GnomAD database, including 11,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (681 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10505 hom.)
• Consequence: TMC1 NM_138691.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.29

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-72816160-C-T is Benign according to our data. Variant chr9-72816160-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72816160-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1713C>T	p.Phe571Phe	synonymous_variant	Exon 19 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1716C>T	p.Phe572Phe	synonymous_variant	Exon 16 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1713C>T	p.Phe571Phe	synonymous_variant	Exon 19 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13180 AN: 152082 Hom.: 680 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0842

GnomAD3 exomes AF: 0.0890 AC: 22356 AN: 251322 Hom.: 1310 AF XY: 0.0893 AC XY: 12127 AN XY: 135822

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.00930

Gnomad SAS exome AF: 0.0321

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.114 AC: 166273 AN: 1460372 Hom.: 10505 Cov.: 31 AF XY: 0.112 AC XY: 81266 AN XY: 726570

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.0498

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.0937

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0866 AC: 13176 AN: 152198 Hom.: 681 Cov.: 32 AF XY: 0.0839 AC XY: 6243 AN XY: 74402

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.0633

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.0326

Gnomad4 FIN AF: 0.0867

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.0829

Alfa AF: 0.117 Hom.: 597

Bravo AF: 0.0858

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 36 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 7 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.6
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34532421; hg19: chr9-75431076;