rs727505247

Positions:

chr11-17509547-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2PM5BP4_ModerateBP6

The NM_153676.4(USH1C):c.1822C>T(p.Pro608Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,449,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P608R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.34

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17509546-G-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.16960871).

BP6

Variant 11-17509547-G-A is Benign according to our data. Variant chr11-17509547-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr11-17509547-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.1822C>T	p.Pro608Ser	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 linkuse as main transcript	c.1285-7567C>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.1822C>T	p.Pro608Ser	missense_variant	18/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.1285-7567C>T		intron_variant		1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151716

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000335

AC:

AN:

238852

Hom.:

AF XY:

0.0000309

AC XY:

AN XY:

129494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000278

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1449326

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

719498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000901

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000472

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.00000996

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

151716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74060

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2014

Variant classified as Uncertain Significance - Favor Benign. The Pro608Ser varia nt in USH1C has not been previously reported in individuals with hearing loss, a nd data from large population studies is insufficient to assess the frequency of this variant. Proline (Pro) at position 608 is not conserved in evolutionarily distant species, raising the possibility that a change at this position may be t olerated. Additional computational prediction tools suggest that the Pro608Ser v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. In summary, while the clinical significance of th e Pro608Ser variant is uncertain, these data suggest that it is more likely to b e benign. -

Usher syndrome type 1C

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Mar 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.061

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.69

M_CAP

Benign

0.045

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.73

D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.59

REVEL

Benign

0.045

Sift

Benign

0.14

Sift4G

Uncertain

0.034

Vest4

0.39

MutPred

0.17

Loss of catalytic residue at P608 (P = 0.0069);

MVP

0.46

MPC

0.068

ClinPred

0.53

GERP RS

4.9

gMVP

0.30

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