rs28941781

Variant names:

• chr3-46709188-C-T
• rs28941781
• NM_147196.3:c.274C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_147196.3(TMIE):​c.274C>T​(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Transmembrane inner ear expressed protein (size 128) in uniprot entity TMIE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_147196.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 3-46709188-C-T is Pathogenic according to our data. Variant chr3-46709188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3392.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr3-46709188-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.274C>T	p.Arg92Trp	missense_variant	Exon 3 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 4		NP_001357453.1
TMIE	NM_001370525.1	c.115C>T	p.Arg39Trp	missense_variant	Exon 4 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.274C>T	p.Arg92Trp	missense_variant	Exon 3 of 4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.172C>T	p.Arg58Trp	missense_variant	Exon 2 of 2			ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249468 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135370

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461800 Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 6 Pathogenic:2

Sep 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 07, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.0	.;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0070	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	.;D;D
Vest4		0.95
MutPred		0.76		.;Loss of disorder (P = 0.0098);Loss of disorder (P = 0.0098);
MVP		0.89
MPC		0.99
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.35
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs28941781; hg19: chr3-46750678;