rs375180950

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_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. 12/21 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 6
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMIE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147196.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMIE	NM_147196.3	MANE Select	c.59T>A	p.Val20Glu	missense	Exon 1 of 4	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1		c.-66-4244T>A		intron	N/A	NP_001357453.1	A0A2R8YDZ8
TMIE	NM_001370525.1		c.-66-4244T>A		intron	N/A	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000643606.3	MANE Select	c.59T>A	p.Val20Glu	missense	Exon 1 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.-66-4244T>A		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8

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

GnomAD2 exomes

AF:

0.00242

AC:

AN:

826

AF XY:

0.00490

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 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

African (AFR)

AF:

0.00434

AC:

101

AN:

23272

American (AMR)

AF:

0.000233

AC:

AN:

8590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15500

East Asian (EAS)

AF:

0.00

AC:

AN:

26722

South Asian (SAS)

AF:

0.00

AC:

AN:

35702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25678

Middle Eastern (MID)

AF:

0.000265

AC:

AN:

3778

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

955200

Other (OTH)

AF:

0.000279

AC:

AN:

46520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

151934

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00362

AC:

150

AN:

41394

American (AMR)

AF:

0.000458

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.10

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.0

PhyloP100

0.15

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.59

REVEL

Uncertain

0.35

Sift

Benign

0.037

Sift4G

Uncertain

0.010

Polyphen

0.0060

Vest4

0.43

MVP

0.46

MPC

0.45

ClinPred

0.018

GERP RS

-0.48

PromoterAI

0.065

Neutral

(source)

Varity_R

0.14

gMVP

0.71

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over