rs727503483

Variant names:

• chr9-72792318-C-A
• rs727503483
• NM_138691.3:c.1532C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-72792318-C-A
• chr9-72792318-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_138691.3(TMC1):​c.1532C>A​(p.Pro511His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P511L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.93
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_138691.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-72792318-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 402278.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 9-72792318-C-A is Pathogenic according to our data. Variant chr9-72792318-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165436.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1532C>A	p.Pro511His	missense_variant	Exon 17 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1535C>A	p.Pro512His	missense_variant	Exon 14 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1532C>A	p.Pro511His	missense_variant	Exon 17 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:1

Aug 01, 2020

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

TMC1 c.1532C>A, p.P511H alters a highly conserved residue in TMC1. The variant is compound heterozygous with TMC1 c.100C>T, p.R34* in 2 Palestinian children, one with moderate HL and the other with profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -

not specified Uncertain:1

Jan 23, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro511His variant has been reported in 1 Libyan individual by our laboratory. The variant was identified in the homozygous state, segregated in an affected sibling, and was confirmed heterozygous in the unaffected parents. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2, PP1, PP3, PM3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;.;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.6	M;M;.;M;.
PhyloP100		4.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.9	D;.;.;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;.;D;.
Sift4G	Uncertain	0.012	D;.;.;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.65
MutPred		0.37		Gain of helix (P = 0.0893);Gain of helix (P = 0.0893);.;Gain of helix (P = 0.0893);.;
MVP		0.88
MPC		0.40
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.65
Mutation Taster		=9/91	disease causing

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: rs727503483; hg19: chr9-75407234;