NM_001370524.1:c.-66-4749delC

Variant names:

• chr3-46701031-GC-G
• rs34094160
• NM_001370524.1:c.-66-4749delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001370524.1(TMIE):​c.-66-4749delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 146,250 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0089 (19 hom., cov: 30)
• Consequence: TMIE NM_001370524.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.439
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 3-46701031-GC-G is Benign according to our data. Variant chr3-46701031-GC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1189555.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00885 (1295/146250) while in subpopulation AFR AF = 0.0276 (1096/39702). AF 95% confidence interval is 0.0262. There are 19 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.-66-4749delC		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4749delC		intron	N/A	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000644830.1		c.-66-4758delC		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1289 AN: 146156 Hom.: 19 Cov.: 30

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00352

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00159

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.000305

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.00905

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00885 AC: 1295 AN: 146250 Hom.: 19 Cov.: 30 AF XY: 0.00865 AC XY: 615 AN XY: 71102

African (AFR) AF: 0.0276 AC: 1096 AN: 39702

American (AMR) AF: 0.00351 AC: 51 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00140 AC: 7 AN: 5010

South Asian (SAS) AF: 0.00153 AC: 7 AN: 4578

European-Finnish (FIN) AF: 0.000305 AC: 3 AN: 9836

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.00164 AC: 108 AN: 66044

Other (OTH) AF: 0.00946 AC: 19 AN: 2008

Alfa AF: 0.000783 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44

Splicing

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

Other links and lift over

dbSNP: rs34094160; hg19: chr3-46742521; COSMIC: COSV58406254; COSMIC: COSV58406254;