rs397517867

Variant names:

• chr3-46701521-G-A
• rs397517867
• NM_147196.3:c.34G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-46701521-G-A
• chr3-46701521-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147196.3(TMIE):​c.34G>A​(p.Val12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000512 in 1,171,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12908924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.34G>A	p.Val12Met	missense_variant	Exon 1 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.-66-4269G>A		intron_variant	Intron 1 of 3		NP_001357453.1
TMIE	NM_001370525.1	c.-66-4269G>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	c.34G>A	p.Val12Met	missense_variant	Exon 1 of 4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.-66-4269G>A		intron_variant	Intron 1 of 3			ENSP00000495111.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000512 AC: 6 AN: 1171398 Hom.: 0 Cov.: 30 AF XY: 0.00000355 AC XY: 2 AN XY: 563850

African (AFR) AF: 0.00 AC: 0 AN: 23448

American (AMR) AF: 0.00 AC: 0 AN: 8760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16018

East Asian (EAS) AF: 0.00 AC: 0 AN: 26870

South Asian (SAS) AF: 0.00 AC: 0 AN: 43640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00000514 AC: 5 AN: 972940

Other (OTH) AF: 0.0000209 AC: 1 AN: 47950

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34G>A (p.V12M) alteration is located in exon 1 (coding exon 1) of the TMIE gene. This alteration results from a G to A substitution at nucleotide position 34, causing the valine (V) at amino acid position 12 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.49	.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.12	.;N
REVEL	Benign	0.24
Sift	Benign	0.056	.;T
Sift4G	Benign	0.24	.;T
Polyphen		0.0080	B;B
Vest4		0.17
MutPred		0.28		Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);
MVP		0.29
MPC		0.28
ClinPred		0.18	T
GERP RS		2.3
PromoterAI		0.035	Neutral
Varity_R		0.056
gMVP		0.37
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs397517867; hg19: chr3-46743011; COSMIC: COSV58405275;