rs145448362

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_173477.5(USH1G):c.83C>T(p.Pro28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,566,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 9.99

Variant links:

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G links:

OTOP2 (HGNC:19657): (otopetrin 2) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

OTOP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.081706524).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000605 (92/152186) while in subpopulation NFE AF= 0.00126 (86/68028). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5 linkuse as main transcript	c.83C>T	p.Pro28Leu	missense_variant	1/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 linkuse as main transcript	c.-174C>T		5_prime_UTR_variant	1/3		NP_001269418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
USH1G	ENST00000614341.5 linkuse as main transcript	c.83C>T	p.Pro28Leu	missense_variant	1/3	1	NM_173477.5	ENSP00000480279	P1
OTOP2	ENST00000580223.2 linkuse as main transcript	c.-274G>A		5_prime_UTR_variant	1/5	1		ENSP00000463837
USH1G	ENST00000579243.1 linkuse as main transcript	c.83C>T	p.Pro28Leu	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000462568

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00126

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000757

AC:

138

AN:

182298

Hom.:

AF XY:

0.000758

AC XY:

AN XY:

97570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000364

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:

0.00161

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.00104

AC:

1472

AN:

1414288

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

747

AN XY:

698568

show subpopulations

Gnomad4 AFR exome

AF:

0.0000926

Gnomad4 AMR exome

AF:

0.000260

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.000753

GnomAD4 genome

AF:

0.000605

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.000699

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000419

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the USH1G protein (p.Pro28Leu). This variant is present in population databases (rs145448362, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17896313, 22135276, 28224992). ClinVar contains an entry for this variant (Variation ID: 48139). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH1G protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 25, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	This variant is associated with the following publications: (PMID: 17896313, 28224992) -

Usher syndrome type 1G

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 30, 2021	The USH1G c.83C>T; p.Pro28Leu variant (rs145448362) is reported in the literature in several individuals affected with Usher syndrome or retinitis pigmentosa, although a second variant was not reported in any individuals (Aller 2007, Haer-Wigman 2017, Le Quesne Stabej 2012). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (138/91578 alleles) in the Genome Aggregation Database. The proline at codon 28 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.353). Due to limited information, the clinical significance of the p.Pro28Leu variant is uncertain at this time. References: Aller et al. Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome. Ophthalmic Genet. 2007 Sep;28(3):151-5. PMID: 17896313. Haer-Wigman et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017 May;25(5):591-599. PMID: 28224992. Le Quesne Stabej et al. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012 Jan;49(1):27-36. PMID: 22135276. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2020

Variant classified as Uncertain Significance - Favor Benign. The p.Pro28Leu variant in USH1G has been reported in the heterozygous state in two individuals with Usher syndrome type 2 (Aller 2007), one individual with retinitis pigmentosa (Haer-Wigman, 2017), and three children with apparently nonsyndromic hearing loss (LMM data). It has also been identified in 0.15% (138/91578) of Europeans chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as likely benign by a clinical lab in ClinVar (Variation ID 48139). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

0.0025

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.040

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

Sift4G

Benign

0.19

Polyphen

0.76

Vest4

0.59

MVP

0.50

ClinPred

0.14

GERP RS

4.1

Varity_R

0.30

gMVP

0.65

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

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