rs121908073

Variant names:

• chr9-72694578-C-G
• rs121908073
• NM_138691.3:c.100C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-72694578-C-G
• chr9-72694578-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_138691.3(TMC1):​c.100C>G​(p.Arg34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14667231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.100C>G	p.Arg34Gly	missense_variant	Exon 7 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.103C>G	p.Arg35Gly	missense_variant	Exon 4 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.100C>G	p.Arg34Gly	missense_variant	Exon 7 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460652 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111356

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	.;.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.;L
PhyloP100		0.094
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.66	N;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.30	T;.;.;T
Sift4G	Benign	0.088	T;.;.;T
Polyphen		0.96	D;D;.;D
Vest4		0.44
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);
MVP		0.11
MPC		0.60
ClinPred		0.93	D
GERP RS		3.4
Varity_R		0.090
gMVP		0.49
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121908073; hg19: chr9-75309494;