Genetic Variant TMIE:c.-66-4757C>A (chr3-46701033-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001370524.1(TMIE):c.-66-4757C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0959 in 147,950 control chromosomes in the GnomAD database, including 783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.096 ( 783 hom., cov: 30)

Consequence

TMIE
NM_001370524.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.439

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 3-46701033-C-A is Benign according to our data. Variant chr3-46701033-C-A is described in ClinVar as Benign. ClinVar VariationId is 1258770.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	NM_001370524.1		c.-66-4757C>A		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4757C>A		intron	N/A	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000644830.1		c.-66-4757C>A		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes

AF:

0.0957

AC:

14148

AN:

147838

Hom.:

778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.00442

Gnomad AMR

AF:

0.0894

Gnomad ASJ

AF:

0.0882

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0518

Gnomad MID

AF:

0.128

Gnomad NFE

AF:

0.0697

Gnomad OTH

AF:

0.0967

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0959

AC:

14192

AN:

147950

Hom.:

783

Cov.:

AF XY:

0.0957

AC XY:

6911

AN XY:

72234

show subpopulations

African (AFR)

AF:

0.153

AC:

5937

AN:

38900

American (AMR)

AF:

0.0893

AC:

1339

AN:

14990

Ashkenazi Jewish (ASJ)

AF:

0.0882

AC:

303

AN:

3436

East Asian (EAS)

AF:

0.129

AC:

660

AN:

5100

South Asian (SAS)

AF:

0.104

AC:

489

AN:

4712

European-Finnish (FIN)

AF:

0.0518

AC:

537

AN:

10370

Middle Eastern (MID)

AF:

0.127

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0698

AC:

4690

AN:

67206

Other (OTH)

AF:

0.0963

AC:

197

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

631

1262

1893

2524

3155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0293

Hom.:

Bravo

AF:

0.0982

Asia WGS

AF:

0.130

AC:

453

AN:

3472

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.4

(source)

DANN

Benign

0.79

PhyloP100

0.44

PromoterAI

-0.0093

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over