rs145448362

chr17-74922991-G-Achr17-74922991-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_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). Synonymous variant affecting the same amino acid position (i.e. P28P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 9.99

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]

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]

ACMG classification

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	UniProt
USH1G	NM_173477.5	c.83C>T	p.Pro28Leu	missense_variant	1/3	ENST00000614341.5
USH1G	NM_001282489.3	c.-174C>T		5_prime_UTR_variant	1/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152186 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.000758 AC XY: 74 AN XY: 97570

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.: 1 Cov.: 31 AF XY: 0.00107 AC XY: 747 AN XY: 698568

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: 92 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 40 AN XY: 74334

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.: 0

Bravo AF: 0.000699

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000419 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

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	Invitae	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	This variant is associated with the following publications: (PMID: 17896313, 28224992) -
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	-	- -

Usher syndrome type 1G Uncertain:2

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. -
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. -

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	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	28
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
Sift4G	Benign	0.19	T
Polyphen		0.76	P
Vest4		0.59
MVP		0.50
ClinPred		0.14	T
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

Other links and lift over

dbSNP: rs145448362; hg19: chr17-72919086;