rs397517869

chr3-46701527-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_147196.3(TMIE):c.40G>A(p.Gly14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,313,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.83

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04318586).
• BP6: Variant 3-46701527-G-A is Benign according to our data. Variant chr3-46701527-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47963.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000591 (90/152324) while in subpopulation AFR AF= 0.00212 (88/41592). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMIE	NM_147196.3	c.40G>A	p.Gly14Ser	missense_variant	1/4	ENST00000643606.3
TMIE	NM_001370524.1	c.-66-4263G>A		intron_variant
TMIE	NM_001370525.1	c.-66-4263G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000643606.3	c.40G>A	p.Gly14Ser	missense_variant	1/4		NM_147196.3	P1
TMIE	ENST00000644830.1	c.-66-4263G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000957

GnomAD4 exome AF: 0.0000457 AC: 53 AN: 1160952 Hom.: 0 Cov.: 30 AF XY: 0.0000376 AC XY: 21 AN XY: 557776

Gnomad4 AFR exome AF: 0.00205

Gnomad4 AMR exome AF: 0.000116

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: 0.00

Gnomad4 OTH exome AF: 0.0000843

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74478

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000620

ExAC AF: 0.0000420 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2013

Variant classified as Uncertain Significance - Favor Benign. The Gly14Ser varian t in TMIE has not been reported in the literature nor previously identified by o ur laboratory. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly14Ser variant may no t impact the protein, though this information is not predictive enough to rule o ut pathogenicity. In summary, the clinical significance of this variant cannot b e determined with certainty; however based upon the weak predicted impact and ab sence of any data supporting pathogenicity, we would lean towards a more likely benign role. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The c.40G>A (p.G14S) 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 40, causing the glycine (G) at amino acid position 14 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	20
Dann	Uncertain	0.97
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.93	N
PrimateAI	Pathogenic	0.80	T
Polyphen		0.0020	B;B
Vest4		0.29
MutPred		0.46		Gain of glycosylation at G14 (P = 0.0045);Gain of glycosylation at G14 (P = 0.0045);
MVP		0.57
MPC		0.28
ClinPred		0.17	T
GERP RS		2.3
Varity_R		0.068
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397517869; hg19: chr3-46743017;