rs397517868

Positions:

• chr3-46709604-GAAGA-GG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP6_Moderate

The NM_147196.3(TMIE):​c.388_391delAAGAinsG​(p.Lys130_Lys131delinsGlu) variant causes a missense, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMIE NM_147196.3 missense, conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51

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 Uncertain_significance. Variant got 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-46709605-AAGA-G is Benign according to our data. Variant chr3-46709605-AAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3	c.388_391delAAGAinsG	p.Lys130_Lys131delinsGlu	missense_variant, conservative_inframe_deletion	4/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.229_232delAAGAinsG	p.Lys77_Lys78delinsGlu	missense_variant, conservative_inframe_deletion	4/4		NP_001357453.1
TMIE	NM_001370525.1	c.229_232delAAGAinsG	p.Lys77_Lys78delinsGlu	missense_variant, conservative_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_391delAAGAinsG	p.Lys130_Lys131delinsGlu	missense_variant, conservative_inframe_deletion	4/4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.229_232delAAGAinsG	p.Lys77_Lys78delinsGlu	missense_variant, conservative_inframe_deletion	4/4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.*310_*313delAAGAinsG		3_prime_UTR_variant	2/2			ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 30, 2012

Lys130_Lys131delinsGlu in exon 4 of TMIE: This variant represents a missense cha nge, Lys131Glu (dbSNP ID rs201683042), that arose on the background of the very common benign variant Lys131del (dbSNP ID rs10578999). Neither variant, nor the combination of variants, is expected to impact the protein as the 3 bp deletion is extremely common and the missense change occurs in a mammal (rabbit has the L ys131Glu in its normal TMIE protein). -

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: rs397517868; hg19: chr3-46751095;