chr3-46701546-T-A

Position:

chr3-46701546-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_147196.3(TMIE):c.59T>A(p.Val20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,292,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V20L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.152

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 Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0046126544).

BP6

Variant 3-46701546-T-A is Benign according to our data. Variant chr3-46701546-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1214509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00105 (160/151934) while in subpopulation AFR AF= 0.00362 (150/41394). AF 95% confidence interval is 0.00315. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMIE	NM_147196.3 linkuse as main transcript	c.59T>A	p.Val20Glu	missense_variant	1/4	ENST00000643606.3
TMIE	NM_001370524.1 linkuse as main transcript	c.-66-4244T>A		intron_variant
TMIE	NM_001370525.1 linkuse as main transcript	c.-66-4244T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000643606.3 linkuse as main transcript	c.59T>A	p.Val20Glu	missense_variant	1/4		NM_147196.3	P1
TMIE	ENST00000644830.1 linkuse as main transcript	c.-66-4244T>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00242

AC:

AN:

826

Hom.:

AF XY:

0.00490

AC XY:

AN XY:

408

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.0556

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

119

AN:

1140962

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

545622

show subpopulations

Gnomad4 AFR exome

AF:

0.00434

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000209

Gnomad4 OTH exome

AF:

0.000279

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

151934

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00362

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.000812

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000798

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.37

.;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.59

.;N

REVEL

Uncertain

0.35

Sift

Benign

0.037

.;D

Sift4G

Uncertain

0.010

.;D

Polyphen

0.0060

B;B

Vest4

0.43

MVP

0.46

MPC

0.45

ClinPred

0.018

GERP RS

-0.48

Varity_R

0.14

gMVP

0.71

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over