3-46701451-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147196.3(TMIE):c.-37C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,387,772 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.026 (526 hom.)
• Consequence: TMIE NM_147196.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-46701451-C-A is Benign according to our data. Variant chr3-46701451-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 345547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0192 (2923/152268) while in subpopulation NFE AF= 0.0316 (2147/67994). AF 95% confidence interval is 0.0305. There are 42 homozygotes in gnomad4. There are 1359 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMIE	NM_147196.3	c.-37C>A		5_prime_UTR_variant	1/4	ENST00000643606.3
TMIE	NM_001370524.1	c.-66-4339C>A		intron_variant
TMIE	NM_001370525.1	c.-66-4339C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000643606.3	c.-37C>A		5_prime_UTR_variant	1/4		NM_147196.3	P1
TMIE	ENST00000644830.1	c.-66-4339C>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2923 AN: 152160 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0282 AC: 1106 AN: 39254 Hom.: 17 AF XY: 0.0284 AC XY: 673 AN XY: 23726

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0226

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0263 AC: 32536 AN: 1235504 Hom.: 526 Cov.: 28 AF XY: 0.0264 AC XY: 15978 AN XY: 604382

Gnomad4 AFR exome AF: 0.00419

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.0000371

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0192 AC: 2923 AN: 152268 Hom.: 42 Cov.: 32 AF XY: 0.0183 AC XY: 1359 AN XY: 74456

Gnomad4 AFR AF: 0.00510

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00704 Hom.: 1

Bravo AF: 0.0184

Asia WGS AF: 0.00842 AC: 30 AN: 3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.8
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs530579940; hg19: chr3-46742941;