rs45552041

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Publications

2 publications found

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 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

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 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 VariationId is 678907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0121

AC:

115

AN:

9520

American (AMR)

AF:

0.0136

AC:

189

AN:

13860

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

277

AN:

6128

East Asian (EAS)

AF:

0.00950

AC:

AN:

6950

South Asian (SAS)

AF:

0.0179

AC:

610

AN:

34166

European-Finnish (FIN)

AF:

0.0665

AC:

705

AN:

10598

Middle Eastern (MID)

AF:

0.0500

AC:

AN:

1060

European-Non Finnish (NFE)

AF:

0.0368

AC:

13866

AN:

376836

Other (OTH)

AF:

0.0397

AC:

717

AN:

18054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

827

1654

2480

3307

4134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00570

AC:

318

AN:

55774

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

154

AN XY:

26886

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00175

AC:

AN:

14818

American (AMR)

AF:

0.00518

AC:

AN:

5596

Ashkenazi Jewish (ASJ)

AF:

0.00424

AC:

AN:

1180

East Asian (EAS)

AF:

0.00234

AC:

AN:

1284

South Asian (SAS)

AF:

0.00473

AC:

AN:

1690

European-Finnish (FIN)

AF:

0.00952

AC:

AN:

2836

Middle Eastern (MID)

AF:

0.0192

AC:

AN:

104

European-Non Finnish (NFE)

AF:

0.00770

AC:

208

AN:

27028

Other (OTH)

AF:

0.00744

AC:

AN:

806

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.3

(source)

DANN

Benign

0.75

PhyloP100

-0.073

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over