3-46701579-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_147196.3(TMIE):c.92A>G(p.Glu31Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 1,281,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: TMIE NM_147196.3 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.66

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-46701579-A-G is Pathogenic according to our data. Variant chr3-46701579-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46701579-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMIE	NM_147196.3	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	1/4	ENST00000643606.3
TMIE	NM_001370524.1	c.-66-4211A>G		intron_variant
TMIE	NM_001370525.1	c.-66-4211A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000643606.3	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	1/4		NM_147196.3	P1
TMIE	ENST00000644830.1	c.-66-4211A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151356 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000885 AC: 10 AN: 1130144 Hom.: 0 Cov.: 30 AF XY: 0.00000928 AC XY: 5 AN XY: 538700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000653

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151356 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73938

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 16, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 372538). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 16389551, 24416283). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 31 of the TMIE protein (p.Glu31Gly). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2015	The E31G pathogenic variant in the TMIE gene has been reported previously in several individuals with hearing loss who were homozygous for this variant (Santos et al., 2006; Ganapathy et al., 20140. The E31G variant was not observed in approximately 4,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E31G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E31G as a pathogenic variant. -

Autosomal recessive nonsyndromic hearing loss 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.E31G in TMIE (NM_147196.2) has been previously reported in homozygous form in patients affected with sensorineural hearing loss including those of Indian origin (Santos et al, 2006; Ganapathy et al, 2014). The variant has been submiited to ClinVar as Pathogenic but no functional studies have been performed. The p.E31G variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glutamic acid and glycine. In silico analsyis predict a damaging effect while the residue is semi-conserved across species. For these reasons, this variant has been classified as Likely Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.67	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
Polyphen		0.97	D;D
Vest4		0.73
MutPred		0.67		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.82
MPC		0.47
ClinPred		0.90	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -35
DS_DL_spliceai		0.49		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517839; hg19: chr3-46743069;