3-46701257-G-A

Position:

• chr3-46701257-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370524.1(TMIE):​c.-66-4533G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0493 in 424,614 control chromosomes in the GnomAD database, including 885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (298 hom., cov: 31)
  • Exomes 𝑓: 0.050 (587 hom.)
• Consequence: TMIE NM_001370524.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169

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=-0.92).
• BP6: Variant 3-46701257-G-A is Benign according to our data. Variant chr3-46701257-G-A is described in ClinVar as [Benign]. Clinvar id is 1265561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMIE	NM_001370524.1	c.-66-4533G>A		intron_variant
TMIE	NM_001370525.1	c.-66-4533G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000644830.1	c.-66-4533G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7364 AN: 152042 Hom.: 299 Cov.: 31

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0498 AC: 13564 AN: 272464 Hom.: 587 AF XY: 0.0531 AC XY: 7596 AN XY: 143034

Gnomad4 AFR exome AF: 0.00767

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0628

Gnomad4 EAS exome AF: 0.00365

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0865

Gnomad4 NFE exome AF: 0.0437

Gnomad4 OTH exome AF: 0.0431

GnomAD4 genome AF: 0.0484 AC: 7360 AN: 152150 Hom.: 298 Cov.: 31 AF XY: 0.0521 AC XY: 3878 AN XY: 74376

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0919

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0585

Gnomad4 OTH AF: 0.0469

Alfa AF: 0.0476 Hom.: 25

Bravo AF: 0.0378

Asia WGS AF: 0.0450 AC: 156 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.86

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs192733532; hg19: chr3-46742747;