rs150567427

chr11-17505950-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_Moderate PP3_Strong BS2

The NM_153676.4(USH1C):c.2014-1G>A variant causes a splice acceptor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: 5.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.044074073 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.2014-1G>A		splice_acceptor_variant		ENST00000005226.12
USH1C	NM_005709.4	c.1285-3970G>A		intron_variant		ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2014-1G>A		splice_acceptor_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.1285-3970G>A		intron_variant		1	NM_005709.4	P1

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

GnomAD3 exomes AF: 0.000418 AC: 105 AN: 251310 Hom.: 1 AF XY: 0.000346 AC XY: 47 AN XY: 135872

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 SAS 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

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000480

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

Gnomad4 AFR AF: 0.00613

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000948

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	Has not been previously reported as pathogenic or benign to our knowledge -

Usher syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2014

The 2014-1G>A variant in USH1C has not been previously reported in individuals w ith hearing loss. It was identified in 0.5% (22/4400) of African American chromo somes by the NHLBI Exome Sequencing Project and in 1.6% (2/122) of African Ameri can chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; dbSNP rs150567427). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. This variant occurs in the invariant region (-1/2) of the 3? splice consensus sequence and c omputational tools suggest an impact to splicing. In summary, while this variant may impact splicing, its frequency in the general population suggests a benign role; therefore, additional information is needed to determine the clinical sign ificance of the 2014-1G>A variant. -

Usher syndrome type 1C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Baylor Genetics

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- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		4.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs150567427; hg19: chr11-17527497;