3-46701501-C-G

Variant names:

• chr3-46701501-C-G
• rs948846775
• NM_147196.3:c.14C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_147196.3(TMIE):​c.14C>G​(p.Pro5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,342,766 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.476
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02748692).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	NM_147196.3	MANE Select	c.14C>G	p.Pro5Arg	missense	Exon 1 of 4	NP_671729.2	Q8NEW7
	TMIE	NM_001370524.1		c.-66-4289C>G		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4289C>G		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.14C>G	p.Pro5Arg	missense	Exon 1 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.-66-4289C>G		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

GnomAD2 exomes AF: 0.000246 AC: 1 AN: 4068 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00595

GnomAD4 exome AF: 0.00000252 AC: 3 AN: 1190654 Hom.: 0 Cov.: 30 AF XY: 0.00000522 AC XY: 3 AN XY: 575126

African (AFR) AF: 0.00 AC: 0 AN: 23820

American (AMR) AF: 0.000101 AC: 1 AN: 9862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16694

East Asian (EAS) AF: 0.00 AC: 0 AN: 26952

South Asian (SAS) AF: 0.0000207 AC: 1 AN: 48380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 982888

Other (OTH) AF: 0.0000205 AC: 1 AN: 48844

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.4
DANN	Benign	0.70
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.48
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.18
Sift	Benign	0.93	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.28		Gain of MoRF binding (P = 2e-04)
MVP		0.34
MPC		0.30
ClinPred		0.046	T
GERP RS		-6.1
PromoterAI		-0.088	Neutral
Varity_R		0.018
gMVP		0.38
Mutation Taster		=99/1	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: rs948846775; hg19: chr3-46742991;