rs1207247951

Variant names:

• chr11-17517464-TC-T
• rs1207247951
• NM_005709.4:c.1220delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005709.4(USH1C):​c.1220delG​(p.Gly407GlufsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_005709.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.47
• Publications: 2 publications found

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17517464-TC-T is Pathogenic according to our data. Variant chr11-17517464-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 555064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005709.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_005709.4	MANE Plus Clinical	c.1220delG	p.Gly407GlufsTer58	frameshift	Exon 15 of 21	NP_005700.2
	USH1C	NM_153676.4	MANE Select	c.1211-1175delG		intron	N/A	NP_710142.1
	USH1C	NM_001440679.1		c.1253delG	p.Gly418GlufsTer38	frameshift	Exon 15 of 22	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1220delG	p.Gly407GlufsTer58	frameshift	Exon 15 of 21	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1163delG	p.Gly388GlufsTer58	frameshift	Exon 14 of 20	ENSP00000436934.1
	USH1C	ENST00000527720.5	TSL:1	c.1127delG	p.Gly376GlufsTer58	frameshift	Exon 14 of 20	ENSP00000432944.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 215712 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440504 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 714100

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.00 AC: 0 AN: 41998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 39020

South Asian (SAS) AF: 0.00 AC: 0 AN: 82604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100782

Other (OTH) AF: 0.00 AC: 0 AN: 59688

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Usher syndrome type 1C (2)
2	-	-	Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 18A (1)
1	-	-	not provided (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1207247951; hg19: chr11-17539011;