NM_138691.3:c.1763+3A>G

Variant names:

• chr9-72816213-A-G
• rs370898981
• NM_138691.3:c.1763+3A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_138691.3(TMC1):​c.1763+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00076 in 1,613,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: TMC1 NM_138691.3 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.04
• Publications: 11 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-72816213-A-G is Pathogenic according to our data. Variant chr9-72816213-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 47864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1763+3A>G		splice_region intron	N/A	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.1763+3A>G		splice_region intron	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.1763+3A>G		splice_region intron	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.1763+3A>G		splice_region intron	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000613 AC: 154 AN: 251290 AF XY: 0.000663

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000786 AC: 1148 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.000755 AC XY: 549 AN XY: 726848

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000921 AC: 1024 AN: 1111328

Other (OTH) AF: 0.000679 AC: 41 AN: 60354

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74506

African (AFR) AF: 0.000120 AC: 5 AN: 41594

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000715 Hom.: 1

Bravo AF: 0.000438

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Autosomal recessive nonsyndromic hearing loss 7 (3)
2	-	-	Autosomal recessive nonsyndromic hearing loss 7;C1847626:Autosomal dominant nonsyndromic hearing loss 36 (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 36 (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.95
PhyloP100		5.0
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: -3

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

Other links and lift over

dbSNP: rs370898981; hg19: chr9-75431129;