rs2355022

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000527720.5(USH1C):c.-104G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,379,894 control chromosomes in the GnomAD database, including 12,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 982 hom., cov: 31)

Exomes 𝑓: 0.12 ( 11686 hom. )

Consequence

USH1C
ENST00000527720.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.769

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 11-17533369-C-A is Benign according to our data. Variant chr11-17533369-C-A is described in ClinVar as Benign. ClinVar VariationId is 262735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.37-47G>T		intron_variant	Intron 1 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 link	c.37-47G>T		intron_variant	Intron 1 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.37-47G>T		intron_variant	Intron 1 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9 link	c.37-47G>T		intron_variant	Intron 1 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15345

AN:

146812

Hom.:

980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0712

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0860

Gnomad ASJ

AF:

0.0852

Gnomad EAS

AF:

0.0637

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.138

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.0968

GnomAD2 exomes

AF:

0.126

AC:

29540

AN:

233934

AF XY:

0.134

show subpopulations

Gnomad AFR exome

AF:

0.0771

Gnomad AMR exome

AF:

0.0743

Gnomad ASJ exome

AF:

0.0942

Gnomad EAS exome

AF:

0.0595

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.125

AC:

153849

AN:

1232970

Hom.:

11686

Cov.:

AF XY:

0.129

AC XY:

80407

AN XY:

625138

show subpopulations

African (AFR)

AF:

0.0625

AC:

1807

AN:

28924

American (AMR)

AF:

0.0756

AC:

3345

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.0903

AC:

2230

AN:

24690

East Asian (EAS)

AF:

0.0580

AC:

2221

AN:

38304

South Asian (SAS)

AF:

0.265

AC:

21761

AN:

82032

European-Finnish (FIN)

AF:

0.130

AC:

6050

AN:

46664

Middle Eastern (MID)

AF:

0.111

AC:

580

AN:

5242

European-Non Finnish (NFE)

AF:

0.120

AC:

109115

AN:

910080

Other (OTH)

AF:

0.128

AC:

6740

AN:

52766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

6892

13784

20677

27569

34461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3720

7440

11160

14880

18600

<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:

0.104

AC:

15346

AN:

146924

Hom.:

982

Cov.:

AF XY:

0.108

AC XY:

7736

AN XY:

71818

show subpopulations

African (AFR)

AF:

0.0710

AC:

2636

AN:

37106

American (AMR)

AF:

0.0859

AC:

1290

AN:

15012

Ashkenazi Jewish (ASJ)

AF:

0.0852

AC:

295

AN:

3462

East Asian (EAS)

AF:

0.0637

AC:

327

AN:

5134

South Asian (SAS)

AF:

0.263

AC:

1257

AN:

4772

European-Finnish (FIN)

AF:

0.137

AC:

1446

AN:

10518

Middle Eastern (MID)

AF:

0.134

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.116

AC:

7835

AN:

67688

Other (OTH)

AF:

0.0997

AC:

203

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

599

1199

1798

2398

2997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.0104

Hom.:

Bravo

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 16, 2018

GeneDx

Significance: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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive nonsyndromic hearing loss 18A

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 1C

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.7

(source)

DANN

Benign

0.45

PhyloP100

-0.77

PromoterAI

0.028

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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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