rs727504779

Positions:

• chr3-46709583-TAAGAAG-T
• chr3-46709583-T-TAAGAAGAAG
• chr3-46709583-TAAGAAGAAG-T
• chr3-46709583-TAAGAAGAAGAAG-T
• chr3-46709583-T-TAAGAAG
• chr3-46709583-TAAG-T
• chr3-46709583-T-TAAG
• chr3-46709583-TAAGAAGAAGAAGAAG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP6_Very_Strong BS1

The NM_147196.3(TMIE):​c.388_393del​(p.Lys130_Lys131del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,088,952 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 0)
  • Exomes 𝑓: 0.018 (1 hom.)
• Consequence: TMIE NM_147196.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a chain Transmembrane inner ear expressed protein (size 128) in uniprot entity TMIE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_147196.3
• BP6: Variant 3-46709583-TAAGAAG-T is Benign according to our data. Variant chr3-46709583-TAAGAAG-T is described in ClinVar as [Likely_benign]. Clinvar id is 262622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00159 (237/149158) while in subpopulation NFE AF= 0.0018 (121/67160). AF 95% confidence interval is 0.00154. There are 1 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3	c.388_393del	p.Lys130_Lys131del	inframe_deletion	4/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.229_234del	p.Lys77_Lys78del	inframe_deletion	4/4		NP_001357453.1
TMIE	NM_001370525.1	c.229_234del	p.Lys77_Lys78del	inframe_deletion	5/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.388_393del	p.Lys130_Lys131del	inframe_deletion	4/4		NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1	c.229_234del	p.Lys77_Lys78del	inframe_deletion	4/4			ENSP00000495111
TMIE	ENST00000651652.1	c.*310_*315del		3_prime_UTR_variant	2/2			ENSP00000498953

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 235 AN: 149048 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000986

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.00234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00180

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.00926 AC: 1348 AN: 145554 Hom.: 0 AF XY: 0.00915 AC XY: 717 AN XY: 78324

Gnomad AFR exome AF: 0.00882

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00612

Gnomad EAS exome AF: 0.00622

Gnomad SAS exome AF: 0.00888

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.00986

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0183 AC: 17216 AN: 939794 Hom.: 1 AF XY: 0.0177 AC XY: 8215 AN XY: 463448

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.0185

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.00159 AC: 237 AN: 149158 Hom.: 1 Cov.: 0 AF XY: 0.00161 AC XY: 117 AN XY: 72620

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.00107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000989

Gnomad4 SAS AF: 0.000636

Gnomad4 FIN AF: 0.00234

Gnomad4 NFE AF: 0.00180

Gnomad4 OTH AF: 0.00145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10578999; hg19: chr3-46751073;