chr3-46701259-A-C

Variant names:

• chr3-46701259-A-C
• rs7430680
• NM_001370524.1:c.-66-4531A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370524.1(TMIE):​c.-66-4531A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 210,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: TMIE NM_001370524.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 0 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370524.1. 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_001370524.1		c.-66-4531A>C		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4531A>C		intron	N/A	NP_001357454.1	A0A2R8YDZ8
	TMIE	NM_147196.3	MANE Select	c.-229A>C		upstream_gene	N/A	NP_671729.2	Q8NEW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000644830.1		c.-66-4531A>C		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000643606.3	MANE Select	c.-229A>C		upstream_gene	N/A	ENSP00000494576.2	Q8NEW7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000948 AC: 20 AN: 210892 Hom.: 0 AF XY: 0.0000802 AC XY: 9 AN XY: 112150

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000279 AC: 1 AN: 3590

American (AMR) AF: 0.00 AC: 0 AN: 4320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6450

East Asian (EAS) AF: 0.000154 AC: 2 AN: 13014

South Asian (SAS) AF: 0.00 AC: 0 AN: 19728

European-Finnish (FIN) AF: 0.000171 AC: 3 AN: 17554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1146

European-Non Finnish (NFE) AF: 0.0000829 AC: 11 AN: 132662

Other (OTH) AF: 0.000241 AC: 3 AN: 12428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.15
PhyloP100		-1.4
PromoterAI		0.077	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7430680; hg19: chr3-46742749;