NM_138691.3:c.362+2315A>C

Variant names:

• chr9-72702958-A-C
• rs1796991
• NM_138691.3:c.362+2315A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138691.3(TMC1):​c.362+2315A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,720 control chromosomes in the GnomAD database, including 4,263 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4263 hom., cov: 30)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.362+2315A>C		intron_variant	Intron 8 of 23	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.365+2315A>C		intron_variant	Intron 5 of 20		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.362+2315A>C		intron_variant	Intron 8 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34537 AN: 151602 Hom.: 4252 Cov.: 30

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.217

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34571 AN: 151720 Hom.: 4263 Cov.: 30 AF XY: 0.233 AC XY: 17260 AN XY: 74120

African (AFR) AF: 0.281 AC: 11627 AN: 41346

American (AMR) AF: 0.269 AC: 4099 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3464

East Asian (EAS) AF: 0.384 AC: 1970 AN: 5124

South Asian (SAS) AF: 0.329 AC: 1570 AN: 4776

European-Finnish (FIN) AF: 0.224 AC: 2359 AN: 10524

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11254 AN: 67918

Other (OTH) AF: 0.222 AC: 470 AN: 2116

Alfa AF: 0.141 Hom.: 340

Bravo AF: 0.230

Asia WGS AF: 0.344 AC: 1195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.40
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs1796991; hg19: chr9-75317874;