chr3-46709132-C-A

Variant names:

• chr3-46709132-C-A
• rs770957465
• NM_147196.3:c.218C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_147196.3(TMIE):​c.218C>A​(p.Thr73Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.218C>A	p.Thr73Lys	missense_variant	Exon 3 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.59C>A	p.Thr20Lys	missense_variant	Exon 3 of 4		NP_001357453.1
TMIE	NM_001370525.1	c.59C>A	p.Thr20Lys	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.218C>A	p.Thr73Lys	missense_variant	Exon 3 of 4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.59C>A	p.Thr20Lys	missense_variant	Exon 3 of 4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.116C>A	p.Thr39Lys	missense_variant	Exon 2 of 2			ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249248 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135262

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461732 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.7	.;L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.6	.;.;D
REVEL	Pathogenic	0.73
Sift	Benign	0.060	.;.;T
Sift4G	Uncertain	0.0040	.;.;D
Polyphen		1.0	.;D;D
Vest4		0.76
MutPred		0.51		.;Gain of ubiquitination at T73 (P = 0.0192);Gain of ubiquitination at T73 (P = 0.0192);
MVP		0.87
MPC		0.94
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.46
gMVP		0.92

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: rs770957465; hg19: chr3-46750622;