9-72616454-A-G

Position:

• chr9-72616454-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138691.3(TMC1):​c.-219A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 151,232 control chromosomes in the GnomAD database, including 24,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24205 hom., cov: 29)
  • Exomes 𝑓: 0.63 (1 hom.)
• Consequence: TMC1 NM_138691.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.477

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

TMC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 9-72616454-A-G is Benign according to our data. Variant chr9-72616454-A-G is described in ClinVar as [Benign]. Clinvar id is 367250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72616454-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC1	NM_138691.3	c.-219A>G		5_prime_UTR_variant	3/24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.-5A>G		5_prime_UTR_variant	2/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784	c.-219A>G		5_prime_UTR_variant	3/24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83491 AN: 151102 Hom.: 24163 Cov.: 29

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.571

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.553

GnomAD4 exome AF: 0.625 AC: 5 AN: 8 Hom.: 1 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

Gnomad4 AFR exome AF: 0.500

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.553 AC: 83592 AN: 151224 Hom.: 24205 Cov.: 29 AF XY: 0.548 AC XY: 40514 AN XY: 73874

Gnomad4 AFR AF: 0.736

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.454

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.553

Alfa AF: 0.498 Hom.: 18349

Bravo AF: 0.568

Asia WGS AF: 0.495 AC: 1720 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 36 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autosomal recessive nonsyndromic hearing loss 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.60
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7026304; hg19: chr9-75231370;