NM_147196.3:c.-37C>A

Variant names:

• chr3-46701451-C-A
• rs530579940
• NM_147196.3:c.-37C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147196.3(TMIE):​c.-37C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,387,772 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.026 (526 hom.)
• Consequence: TMIE NM_147196.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.19
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-46701451-C-A is Benign according to our data. Variant chr3-46701451-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345547.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 = 0.0192 (2923/152268) while in subpopulation NFE AF = 0.0316 (2147/67994). AF 95% confidence interval is 0.0305. There are 42 homozygotes in GnomAd4. There are 1359 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.-37C>A		5_prime_UTR	Exon 1 of 4	NP_671729.2	Q8NEW7
	TMIE	NM_001370524.1		c.-66-4339C>A		intron	N/A	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-4339C>A		intron	N/A	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000643606.3	MANE Select	c.-37C>A		5_prime_UTR	Exon 1 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.-66-4339C>A		intron	N/A	ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2923 AN: 152160 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0282 AC: 1106 AN: 39254 AF XY: 0.0284

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0263 AC: 32536 AN: 1235504 Hom.: 526 Cov.: 28 AF XY: 0.0264 AC XY: 15978 AN XY: 604382

African (AFR) AF: 0.00419 AC: 103 AN: 24566

American (AMR) AF: 0.0193 AC: 289 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 500 AN: 20170

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26984

South Asian (SAS) AF: 0.0168 AC: 1014 AN: 60470

European-Finnish (FIN) AF: 0.0178 AC: 553 AN: 31002

Middle Eastern (MID) AF: 0.0281 AC: 145 AN: 5168

European-Non Finnish (NFE) AF: 0.0286 AC: 28658 AN: 1001280

Other (OTH) AF: 0.0250 AC: 1273 AN: 50862

GnomAD4 genome AF: 0.0192 AC: 2923 AN: 152268 Hom.: 42 Cov.: 32 AF XY: 0.0183 AC XY: 1359 AN XY: 74456

African (AFR) AF: 0.00510 AC: 212 AN: 41556

American (AMR) AF: 0.0150 AC: 229 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4830

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10622

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0316 AC: 2147 AN: 67994

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.00704 Hom.: 1

Bravo AF: 0.0184

Asia WGS AF: 0.00842 AC: 30 AN: 3460

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 6 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.8
DANN	Benign	0.67
PhyloP100		-3.2
PromoterAI		-0.064	Neutral
Mutation Taster		=296/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs530579940; hg19: chr3-46742941;