NM_001370524.1:c.-66-4532C>A

Variant names:

• chr3-46701258-C-A
• rs184330048
• NM_001370524.1:c.-66-4532C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370524.1(TMIE):​c.-66-4532C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 416,438 control chromosomes in the GnomAD database, including 897 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: 0.052 (599 hom.)
• Consequence: TMIE NM_001370524.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80
• Publications: 2 publications found

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]

TMIE Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 6

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-46701258-C-A is Benign according to our data. Variant chr3-46701258-C-A is described in ClinVar as Benign. ClinVar VariationId is 1262078.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370524.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	NM_001370524.1		c.-66-4532C>A		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4532C>A		intron	N/A	NP_001357454.1	A0A2R8YDZ8
	TMIE	NM_147196.3	MANE Select	c.-230C>A		upstream_gene	N/A	NP_671729.2	Q8NEW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000644830.1		c.-66-4532C>A		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000643606.3	MANE Select	c.-230C>A		upstream_gene	N/A	ENSP00000494576.2	Q8NEW7

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7365 AN: 151956 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: 0.122

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0517 AC: 13679 AN: 264374 Hom.: 599 AF XY: 0.0552 AC XY: 7667 AN XY: 139014

African (AFR) AF: 0.00809 AC: 48 AN: 5930

American (AMR) AF: 0.0199 AC: 118 AN: 5918

Ashkenazi Jewish (ASJ) AF: 0.0655 AC: 544 AN: 8300

East Asian (EAS) AF: 0.00382 AC: 73 AN: 19092

South Asian (SAS) AF: 0.125 AC: 2575 AN: 20570

European-Finnish (FIN) AF: 0.0908 AC: 1971 AN: 21706

Middle Eastern (MID) AF: 0.0849 AC: 119 AN: 1402

European-Non Finnish (NFE) AF: 0.0454 AC: 7511 AN: 165272

Other (OTH) AF: 0.0445 AC: 720 AN: 16184

GnomAD4 genome AF: 0.0484 AC: 7361 AN: 152064 Hom.: 298 Cov.: 31 AF XY: 0.0521 AC XY: 3875 AN XY: 74328

African (AFR) AF: 0.0101 AC: 419 AN: 41512

American (AMR) AF: 0.0297 AC: 454 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3470

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5154

South Asian (SAS) AF: 0.122 AC: 590 AN: 4822

European-Finnish (FIN) AF: 0.126 AC: 1333 AN: 10548

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.0586 AC: 3979 AN: 67946

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0476 Hom.: 25

Bravo AF: 0.0378

Asia WGS AF: 0.0450 AC: 156 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.52
PhyloP100		-1.8
PromoterAI		0.061	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs184330048; hg19: chr3-46742748;