rs34532421

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 47863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	NM_138691.3	MANE Select	c.1713C>T	p.Phe571Phe	synonymous	Exon 19 of 24	NP_619636.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.1713C>T	p.Phe571Phe	synonymous	Exon 19 of 24	ENSP00000297784.6
	TMC1	ENST00000340019.4	TSL:5	c.1713C>T	p.Phe571Phe	synonymous	Exon 17 of 22	ENSP00000341433.3
	TMC1	ENST00000645208.2		c.1713C>T	p.Phe571Phe	synonymous	Exon 18 of 23	ENSP00000494684.1

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

GnomAD2 exomes AF: 0.0890 AC: 22356 AN: 251322 AF XY: 0.0893

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 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

African (AFR) AF: 0.0378 AC: 1263 AN: 33442

American (AMR) AF: 0.0498 AC: 2226 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2918 AN: 26092

East Asian (EAS) AF: 0.0186 AC: 740 AN: 39684

South Asian (SAS) AF: 0.0326 AC: 2812 AN: 86232

European-Finnish (FIN) AF: 0.0937 AC: 5005 AN: 53402

Middle Eastern (MID) AF: 0.0911 AC: 525 AN: 5764

European-Non Finnish (NFE) AF: 0.130 AC: 144492 AN: 1110724

Other (OTH) AF: 0.104 AC: 6292 AN: 60332

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

African (AFR) AF: 0.0404 AC: 1678 AN: 41532

American (AMR) AF: 0.0633 AC: 968 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 380 AN: 3466

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5178

South Asian (SAS) AF: 0.0326 AC: 157 AN: 4820

European-Finnish (FIN) AF: 0.0867 AC: 918 AN: 10590

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8680 AN: 68004

Other (OTH) AF: 0.0829 AC: 175 AN: 2112

Alfa AF: 0.115 Hom.: 721

Bravo AF: 0.0858

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.131

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 36 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.6
DANN	Benign	0.66
PhyloP100		2.3
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34532421; hg19: chr9-75431076; COSMIC: COSV108134927;