3-46701259-A-T

Variant names:

• chr3-46701259-A-T
• rs7430680
• NM_001370524.1:c.-66-4531A>T

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.-66-4531A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 361,318 control chromosomes in the GnomAD database, including 12,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3913 hom., cov: 31)
  • Exomes 𝑓: 0.30 (8935 hom.)
• Consequence: TMIE NM_001370524.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.38
• Publications: 3 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: PanelApp Australia, Ambry Genetics, 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=-0.87).
• BP6: Variant 3-46701259-A-T is Benign according to our data. Variant chr3-46701259-A-T is described in ClinVar as Benign. ClinVar VariationId is 1272920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 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.-66-4531A>T		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4531A>T		intron	N/A	NP_001357454.1	A0A2R8YDZ8
	TMIE	NM_147196.3	MANE Select	c.-229A>T		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.-66-4531A>T		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000643606.3	MANE Select	c.-229A>T		upstream_gene	N/A	ENSP00000494576.2	Q8NEW7

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32138 AN: 150788 Hom.: 3908 Cov.: 31

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.225

GnomAD4 exome AF: 0.302 AC: 63491 AN: 210426 Hom.: 8935 AF XY: 0.301 AC XY: 33666 AN XY: 111900

African (AFR) AF: 0.122 AC: 438 AN: 3576

American (AMR) AF: 0.327 AC: 1408 AN: 4312

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 1818 AN: 6440

East Asian (EAS) AF: 0.311 AC: 4036 AN: 12984

South Asian (SAS) AF: 0.263 AC: 5173 AN: 19680

European-Finnish (FIN) AF: 0.278 AC: 4857 AN: 17500

Middle Eastern (MID) AF: 0.207 AC: 236 AN: 1142

European-Non Finnish (NFE) AF: 0.316 AC: 41885 AN: 132398

Other (OTH) AF: 0.294 AC: 3640 AN: 12394

GnomAD4 genome AF: 0.213 AC: 32146 AN: 150892 Hom.: 3913 Cov.: 31 AF XY: 0.214 AC XY: 15756 AN XY: 73784

African (AFR) AF: 0.0876 AC: 3605 AN: 41138

American (AMR) AF: 0.252 AC: 3834 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 770 AN: 3458

East Asian (EAS) AF: 0.220 AC: 1103 AN: 5022

South Asian (SAS) AF: 0.263 AC: 1247 AN: 4734

European-Finnish (FIN) AF: 0.251 AC: 2613 AN: 10418

Middle Eastern (MID) AF: 0.224 AC: 65 AN: 290

European-Non Finnish (NFE) AF: 0.270 AC: 18262 AN: 67616

Other (OTH) AF: 0.222 AC: 465 AN: 2098

Alfa AF: 0.116 Hom.: 191

Bravo AF: 0.205

Asia WGS AF: 0.218 AC: 750 AN: 3452

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	3.2
DANN	Benign	0.27
PhyloP100		-1.4
PromoterAI		-0.074	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: rs7430680; hg19: chr3-46742749; COSMIC: COSV58405354; COSMIC: COSV58405354;