dbSNP rs45552041: USH1C:c.496+66G>T (chr11-17527157-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153676.4(USH1C):c.496+66G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 2 hom., cov: 0)

Exomes 𝑓: 0.035 ( 383 hom. )

Failed GnomAD Quality Control

Consequence

USH1C
NM_153676.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0730

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 11-17527157-C-A is Benign according to our data. Variant chr11-17527157-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 678907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0057 (318/55774) while in subpopulation NFE AF= 0.0077 (208/27028). AF 95% confidence interval is 0.00684. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.496+66G>T		intron_variant	Intron 5 of 26	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.496+66G>T		intron_variant	Intron 5 of 20	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.496+66G>T		intron_variant	Intron 5 of 26	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.496+66G>T		intron_variant	Intron 5 of 20	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.00572

AC:

319

AN:

55730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00926

Gnomad AMR

AF:

0.00519

Gnomad ASJ

AF:

0.00424

Gnomad EAS

AF:

0.00233

Gnomad SAS

AF:

0.00472

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.0283

Gnomad NFE

AF:

0.00769

Gnomad OTH

AF:

0.00754

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0348

AC:

16598

AN:

477172

Hom.:

383

Cov.:

AF XY:

0.0344

AC XY:

8163

AN XY:

237280

show subpopulations

Gnomad4 AFR exome

AF:

0.0121

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.0452

Gnomad4 EAS exome

AF:

0.00950

Gnomad4 SAS exome

AF:

0.0179

Gnomad4 FIN exome

AF:

0.0665

Gnomad4 NFE exome

AF:

0.0368

Gnomad4 OTH exome

AF:

0.0397

GnomAD4 genome

AF:

0.00570

AC:

318

AN:

55774

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

154

AN XY:

26886

show subpopulations

Gnomad4 AFR

AF:

0.00175

Gnomad4 AMR

AF:

0.00518

Gnomad4 ASJ

AF:

0.00424

Gnomad4 EAS

AF:

0.00234

Gnomad4 SAS

AF:

0.00473

Gnomad4 FIN

AF:

0.00952

Gnomad4 NFE

AF:

0.00770

Gnomad4 OTH

AF:

0.00744

Alfa

AF:

0.0408

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.3

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over