rs150567427

Variant names:

• chr11-17505950-C-T
• rs150567427
• NM_153676.4:c.2014-1G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_153676.4(USH1C):​c.2014-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000323 in 1,614,178 control chromosomes in the GnomAD database, including 6 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: USH1C NM_153676.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 5.40
• 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: Benign. The variant received -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.044444446 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 11-17505950-C-T is Benign according to our data. Variant chr11-17505950-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178566.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (262/152318) while in subpopulation AFR AF = 0.00613 (255/41568). AF 95% confidence interval is 0.00552. There are 2 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. 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
	USH1C	NM_153676.4	MANE Select	c.2014-1G>A		splice_acceptor intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-3970G>A		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1471-3970G>A		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.2014-1G>A		splice_acceptor intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-3970G>A		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1228-3970G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000418 AC: 105 AN: 251310 AF XY: 0.000346

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.000145

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 AF: 0.000178 AC: 260 AN: 1461860 Hom.: 4 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727228

African (AFR) AF: 0.00633 AC: 212 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.000480 AC: 29 AN: 60390

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00170 AC XY: 127 AN XY: 74492

African (AFR) AF: 0.00613 AC: 255 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00196

ESP6500AA AF: 0.00500 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000502 AC: 61

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	not specified (1)
-	-	1	USH1C-related disorder (1)
1	-	-	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		5.4
GERP RS		4.9
Mutation Taster		=69/31	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: -15

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

Other links and lift over

dbSNP: rs150567427; hg19: chr11-17527497;