9-72788378-C-G

Position:

• chr9-72788378-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138691.3(TMC1):​c.924C>G​(p.Asp308Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,984 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D308D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (4 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.190

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012515813).
• BP6: Variant 9-72788378-C-G is Benign according to our data. Variant chr9-72788378-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286752.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.924C>G	p.Asp308Glu	missense_variant	14/24	ENST00000297784.10
TMC1	XM_017014256.2	c.927C>G	p.Asp309Glu	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.924C>G	p.Asp308Glu	missense_variant	14/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251418 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135878

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461768 Hom.: 4 Cov.: 31 AF XY: 0.0000798 AC XY: 58 AN XY: 727180

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74430

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000604

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2019	- -

Autosomal recessive nonsyndromic hearing loss 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant nonsyndromic hearing loss 36 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.16	T;T;.;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.57	N;N;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.89	N;.;.;N;.
REVEL	Benign	0.11
Sift	Benign	0.21	T;.;.;T;.
Sift4G	Benign	0.60	T;.;.;T;.
Polyphen		0.0020	B;B;.;B;.
Vest4		0.30
MutPred		0.22		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;
MVP		0.11
MPC		0.16
ClinPred		0.019	T
GERP RS		4.0
Varity_R		0.12
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs113342704; hg19: chr9-75403294;