3-46705910-G-C

Variant names:

• chr3-46705910-G-C
• rs397517865
• NM_147196.3:c.211+3G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_147196.3(TMIE):​c.211+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMIE NM_147196.3 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.06

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-46705910-G-C is Pathogenic according to our data. Variant chr3-46705910-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-46705910-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.211+3G>C		splice_region_variant, intron_variant	Intron 2 of 3	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.52+3G>C		splice_region_variant, intron_variant	Intron 2 of 3		NP_001357453.1
TMIE	NM_001370525.1	c.52+3G>C		splice_region_variant, intron_variant	Intron 3 of 4		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.211+3G>C		splice_region_variant, intron_variant	Intron 2 of 3		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.52+3G>C		splice_region_variant, intron_variant	Intron 2 of 3			ENSP00000495111.1
TMIE	ENST00000651652.1	c.109+3G>C		splice_region_variant, intron_variant	Intron 1 of 1			ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Jan 18, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 211+3G>C variant in TMIE has not been reported in the literature nor previou sly identified by our laboratory. This variant is located in the 5' splice regio n. Computational tools predict an impact to splicing. In summary, based upon the computational predictions and the presence of a second variant in trans in this individual?s son, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: -37
DS_DL_spliceai		0.64		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517865; hg19: chr3-46747400;