chr3-46705887-C-T

Position:

• chr3-46705887-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BS1_Supporting

The NM_147196.3(TMIE):​c.191C>T​(p.Ser64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 6.51

Genes affected

TMIE (HGNC:30800): (transmembrane inner ear) This gene encodes a transmembrane inner ear protein. Studies in mouse suggest that this gene is required for normal postnatal maturation of sensory hair cells in the cochlea, including correct development of stereocilia bundles. This gene is one of multiple genes responsible for recessive non-syndromic deafness (DFNB), also known as autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a chain Transmembrane inner ear expressed protein (size 128) in uniprot entity TMIE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_147196.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083521634).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000372 (544/1461786) while in subpopulation MID AF= 0.00711 (41/5768). AF 95% confidence interval is 0.00539. There are 1 homozygotes in gnomad4_exome. There are 290 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3	c.191C>T	p.Ser64Leu	missense_variant	2/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.32C>T	p.Ser11Leu	missense_variant	2/4		NP_001357453.1
TMIE	NM_001370525.1	c.32C>T	p.Ser11Leu	missense_variant	3/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.191C>T	p.Ser64Leu	missense_variant	2/4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.32C>T	p.Ser11Leu	missense_variant	2/4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.89C>T	p.Ser30Leu	missense_variant	1/2			ENSP00000498953.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000368 AC: 92 AN: 249670 Hom.: 0 AF XY: 0.000443 AC XY: 60 AN XY: 135418

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000372 AC: 544 AN: 1461786 Hom.: 1 Cov.: 32 AF XY: 0.000399 AC XY: 290 AN XY: 727204

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74490

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 64 of the TMIE protein (p.Ser64Leu). This variant is present in population databases (rs189895472, gnomAD 0.06%). This missense change has been observed in individual(s) with deafness (PMID: 24875298). ClinVar contains an entry for this variant (Variation ID: 165460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	This variant is associated with the following publications: (PMID: 24875298) -

Autosomal recessive nonsyndromic hearing loss 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2019	The TMIE c.191C>T; p.Ser64Leu variant (rs189895472) was detected in a patient with recessive hereditary hearing loss in the heterozygous state; however, a likely causative variant in another gene was also identified (Vona 2014). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.04% (identified on 105 out of 281,070 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 165460). The serine at position 64 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Ser64Leu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ser64Leu variant cannot be determined with certainty. -
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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 11, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ser64Leu vari ant in TMIE has been previously reported in the heterozygous state in four indiv iduals with hearing loss; however, an alternate explanation of the hearing loss was identified in two of these individuals (Vona 2014, LMM data). This variant h as been identified across several populations by the Exome Aggregation Consortiu m with a frequency of 0.04% (46/120742) of the total chromosomes (ExAC, http://e xac.broadinstitute.org; dbSNP rs189895472). However, its frequency is not high e nough to rule out a pathogenic role. Computational prediction tools and conserva tion analyses do not provide strong support for or against an impact to the prot ein. In summary, while the clinical significance of the p.Ser64Leu variant is un certain, the identification of the variant in several individuals with an altern ate explanation of the hearing loss suggests it is more likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.83	.;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.40	.;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.50	.;.;T
Sift4G	Uncertain	0.041	.;.;D
Polyphen		0.99	.;D;D
Vest4		0.49
MVP		0.90
MPC		0.52
ClinPred		0.035	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs189895472; hg19: chr3-46747377;