Genetic Variant TMIE:c.-66-4531A>T (chr3-46701259-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001370524.1(TMIE):c.-66-4531A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 361,318 control chromosomes in the GnomAD database, including 12,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3913 hom., cov: 31)

Exomes 𝑓: 0.30 ( 8935 hom. )

Consequence

TMIE
NM_001370524.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.38

Publications

3 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: Ambry Genetics, PanelApp Australia, 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 3-46701259-A-T is Benign according to our data. Variant chr3-46701259-A-T is described in ClinVar as Benign. ClinVar VariationId is 1272920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370524.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMIE	NM_001370524.1		c.-66-4531A>T	intron	N/A	NP_001357453.1	A0A2R8YDZ8
TMIE	NM_001370525.1		c.-66-4531A>T	intron	N/A	NP_001357454.1	A0A2R8YDZ8
TMIE	NM_147196.3	MANE Select	c.-229A>T	upstream_gene	N/A	NP_671729.2	Q8NEW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000644830.1		c.-66-4531A>T		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000643606.3	MANE Select	c.-229A>T		upstream_gene	N/A	ENSP00000494576.2	Q8NEW7

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32138

AN:

150788

Hom.:

3908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0878

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.252

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.224

Gnomad NFE

AF:

0.270

Gnomad OTH

AF:

0.225

GnomAD4 exome

AF:

0.302

AC:

63491

AN:

210426

Hom.:

8935

AF XY:

0.301

AC XY:

33666

AN XY:

111900

show subpopulations

African (AFR)

AF:

0.122

AC:

438

AN:

3576

American (AMR)

AF:

0.327

AC:

1408

AN:

4312

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

1818

AN:

6440

East Asian (EAS)

AF:

0.311

AC:

4036

AN:

12984

South Asian (SAS)

AF:

0.263

AC:

5173

AN:

19680

European-Finnish (FIN)

AF:

0.278

AC:

4857

AN:

17500

Middle Eastern (MID)

AF:

0.207

AC:

236

AN:

1142

European-Non Finnish (NFE)

AF:

0.316

AC:

41885

AN:

132398

Other (OTH)

AF:

0.294

AC:

3640

AN:

12394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

2186

4373

6559

8746

10932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.213

AC:

32146

AN:

150892

Hom.:

3913

Cov.:

AF XY:

0.214

AC XY:

15756

AN XY:

73784

show subpopulations

African (AFR)

AF:

0.0876

AC:

3605

AN:

41138

American (AMR)

AF:

0.252

AC:

3834

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

770

AN:

3458

East Asian (EAS)

AF:

0.220

AC:

1103

AN:

5022

South Asian (SAS)

AF:

0.263

AC:

1247

AN:

4734

European-Finnish (FIN)

AF:

0.251

AC:

2613

AN:

10418

Middle Eastern (MID)

AF:

0.224

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.270

AC:

18262

AN:

67616

Other (OTH)

AF:

0.222

AC:

465

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1258

2516

3773

5031

6289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.116

Hom.:

191

Bravo

AF:

0.205

Asia WGS

AF:

0.218

AC:

750

AN:

3452

ClinVar

ClinVar submissions

Significance: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

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.2

(source)

DANN

Benign

0.27

PhyloP100

-1.4

PromoterAI

-0.074

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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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