3-46709583-TAAGAAGAAGAAGAAG-TAAGAAGAAGAAGAAGAAG

Variant names:

• chr3-46709583-T-TAAG
• rs10578999
• NM_147196.3:c.391_393dupAAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_147196.3(TMIE):​c.391_393dupAAG​(p.Lys131dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: TMIE NM_147196.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.773
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 3-46709583-T-TAAG is Benign according to our data. Variant chr3-46709583-T-TAAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179307.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1506/150044) while in subpopulation AFR AF = 0.0293 (1195/40790). AF 95% confidence interval is 0.0279. There are 26 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.391_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4	NP_671729.2	Q8NEW7
	TMIE	NM_001370524.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	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.391_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000651652.1		c.*313_*315dupAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1	A0A494C1A3

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1498 AN: 149934 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.0698

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00637

Gnomad EAS AF: 0.000591

Gnomad SAS AF: 0.00381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00629

GnomAD2 exomes AF: 0.00599 AC: 872 AN: 145554 AF XY: 0.00539

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00801

Gnomad EAS exome AF: 0.000711

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00483

GnomAD4 exome AF: 0.00239 AC: 3353 AN: 1402534 Hom.: 0 Cov.: 0 AF XY: 0.00224 AC XY: 1567 AN XY: 698872

African (AFR) AF: 0.0326 AC: 1037 AN: 31782

American (AMR) AF: 0.00309 AC: 135 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.00450 AC: 114 AN: 25346

East Asian (EAS) AF: 0.000438 AC: 17 AN: 38818

South Asian (SAS) AF: 0.00257 AC: 218 AN: 84782

European-Finnish (FIN) AF: 0.000174 AC: 9 AN: 51750

Middle Eastern (MID) AF: 0.00320 AC: 18 AN: 5628

European-Non Finnish (NFE) AF: 0.00151 AC: 1600 AN: 1062698

Other (OTH) AF: 0.00353 AC: 205 AN: 58100

GnomAD4 genome AF: 0.0100 AC: 1506 AN: 150044 Hom.: 26 Cov.: 0 AF XY: 0.00930 AC XY: 680 AN XY: 73120

African (AFR) AF: 0.0293 AC: 1195 AN: 40790

American (AMR) AF: 0.00425 AC: 64 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00637 AC: 22 AN: 3452

East Asian (EAS) AF: 0.000592 AC: 3 AN: 5064

South Asian (SAS) AF: 0.00360 AC: 17 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: 0.00190 AC: 128 AN: 67484

Other (OTH) AF: 0.00670 AC: 14 AN: 2090

Alfa AF: 0.00189 Hom.: 1309

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.77
Mutation Taster		=89/11	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; COSMIC: COSV58405725; COSMIC: COSV58405725;