Genetic Variant TMIE:p.Ala2Glu (chr3-46701492-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_147196.3(TMIE):c.5C>A(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,346,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.334

Variant links:

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]

TMIE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16556838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3 link	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 4	ENST00000643606.3	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1 link	c.-66-4298C>A		intron_variant	Intron 1 of 3		NP_001357453.1
TMIE	NM_001370525.1 link	c.-66-4298C>A		intron_variant	Intron 2 of 4		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3 link	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 4		NM_147196.3	ENSP00000494576.2		Q8NEW7
TMIE	ENST00000644830.1 link	c.-66-4298C>A		intron_variant	Intron 1 of 3			ENSP00000495111.1		A0A2R8YDZ8

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

6440

Hom.:

AF XY:

0.00

AC XY:

AN XY:

3932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000331

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000268

AC:

AN:

1194196

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

577490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000348

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.0000408

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.073

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.25

.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.0

N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.29

.;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.067

.;T

Polyphen

0.21

B;B

Vest4

0.25

MutPred

0.26

Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);

MVP

0.66

MPC

0.33

ClinPred

0.12

GERP RS

2.3

Varity_R

0.23

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over