3-46709583-TAAGAAGAAG-T

Variant names:

• chr3-46709583-TAAGAAGAAG-T
• rs10578999
• NM_147196.3:c.385_393delAAGAAGAAG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_147196.3(TMIE):​c.385_393delAAGAAGAAG​(p.Lys129_Lys131del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,552,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: TMIE NM_147196.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.54
• Publications: 21 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 3-46709583-TAAGAAGAAG-T is Benign according to our data. Variant chr3-46709583-TAAGAAGAAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227101.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000373 (56/150058) while in subpopulation SAS AF = 0.00403 (19/4720). AF 95% confidence interval is 0.00264. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147196.3. 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_147196.3	MANE Select	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NP_671729.2	Q8NEW7
	TMIE	NM_001370524.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 5 of 5	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000643606.3	MANE Select	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000651652.1		c.*307_*315delAAGAAGAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1	A0A494C1A3

Frequencies

GnomAD3 genomes AF: 0.000373 AC: 56 AN: 149948 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000399

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00402

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000267

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00129 AC: 188 AN: 145554 AF XY: 0.00175

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.000633

Gnomad EAS exome AF: 0.000534

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.000769

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.000477 AC: 669 AN: 1402350 Hom.: 0 AF XY: 0.000591 AC XY: 413 AN XY: 698780

African (AFR) AF: 0.000126 AC: 4 AN: 31782

American (AMR) AF: 0.000573 AC: 25 AN: 43626

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 7 AN: 25342

East Asian (EAS) AF: 0.000232 AC: 9 AN: 38816

South Asian (SAS) AF: 0.00368 AC: 312 AN: 84778

European-Finnish (FIN) AF: 0.000155 AC: 8 AN: 51738

Middle Eastern (MID) AF: 0.00213 AC: 12 AN: 5626

European-Non Finnish (NFE) AF: 0.000229 AC: 243 AN: 1062548

Other (OTH) AF: 0.000843 AC: 49 AN: 58094

GnomAD4 genome AF: 0.000373 AC: 56 AN: 150058 Hom.: 0 Cov.: 0 AF XY: 0.000383 AC XY: 28 AN XY: 73126

African (AFR) AF: 0.000245 AC: 10 AN: 40804

American (AMR) AF: 0.000398 AC: 6 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3452

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5064

South Asian (SAS) AF: 0.00403 AC: 19 AN: 4720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000267 AC: 18 AN: 67484

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000771 Hom.: 1309

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)
-	-	1	TMIE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=183/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10578999; hg19: chr3-46751073;