rs7022441

Variant names:

• chr9-72521873-G-A
• rs7022441
• NM_138691.3:c.-468G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138691.3(TMC1):​c.-468G>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 0.526 in 152,004 control chromosomes in the GnomAD database, including 21,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21650 hom., cov: 32)
  • Exomes 𝑓: 0.75 (1 hom.)
• Consequence: TMC1 NM_138691.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.156
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AD, Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289993 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 9-72521873-G-A is Benign according to our data. Variant chr9-72521873-G-A is described in ClinVar as Benign. ClinVar VariationId is 367245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. 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
	TMC1	NM_138691.3	MANE Select	c.-468G>A		5_prime_UTR	Exon 1 of 24	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.-468G>A		5_prime_UTR	Exon 1 of 24	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000643676.1		n.266G>A		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000289993	ENST00000819184.1		n.412-435C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79856 AN: 151882 Hom.: 21627 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.526 AC: 79917 AN: 152000 Hom.: 21650 Cov.: 32 AF XY: 0.522 AC XY: 38789 AN XY: 74280

African (AFR) AF: 0.650 AC: 26962 AN: 41458

American (AMR) AF: 0.514 AC: 7849 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1728 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2232 AN: 5176

South Asian (SAS) AF: 0.428 AC: 2060 AN: 4812

European-Finnish (FIN) AF: 0.474 AC: 4985 AN: 10526

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32485 AN: 67978

Other (OTH) AF: 0.537 AC: 1129 AN: 2104

Alfa AF: 0.500 Hom.: 26448

Bravo AF: 0.534

Asia WGS AF: 0.456 AC: 1585 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 36 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 7 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		0.16
PromoterAI		-0.0082	Neutral
Mutation Taster		=292/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7022441; hg19: chr9-75136789;