17-74919578-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_173477.5(USH1G):c.1258C>G(p.Leu420Val) variant causes a missense change. The variant allele was found at a frequency of 0.00188 in 1,612,640 control chromosomes in the GnomAD database, including 6 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. L420L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 6.92

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2744444).
• BP6: Variant 17-74919578-G-C is Benign according to our data. Variant chr17-74919578-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48126.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}. Variant chr17-74919578-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000874 (133/152216) while in subpopulation NFE AF= 0.00163 (111/68046). AF 95% confidence interval is 0.00138. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.1258C>G	p.Leu420Val	missense_variant	2/3	ENST00000614341.5
USH1G	NM_001282489.3	c.949C>G	p.Leu317Val	missense_variant	2/3
USH1G	XM_011524296.2	c.949C>G	p.Leu317Val	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.1258C>G	p.Leu420Val	missense_variant	2/3	1	NM_173477.5	P1
USH1G	ENST00000579243.1	c.*857C>G		3_prime_UTR_variant, NMD_transcript_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000937 AC: 233 AN: 248630 Hom.: 1 AF XY: 0.000895 AC XY: 121 AN XY: 135250

Gnomad AFR exome AF: 0.000378

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00199 AC: 2900 AN: 1460424 Hom.: 6 Cov.: 41 AF XY: 0.00195 AC XY: 1417 AN XY: 726500

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.000874 AC: 133 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74366

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.000895

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000989 AC: 120

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 19, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The USH1G p.Leu420Val variant was identified as a heterozygous variant in 1 of 340 proband chromosomes (frequency: 0.00294) from an individual with Usher syndrome, however two pathogenic variants in the USH2A gene (p.C3090*, p.W3702*) were identified in this individual and were presumed to be the cause of disease (Glockle_2014_PMID:23591405). The variant was identified in dbSNP (ID: rs139897506), ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and EGL Genetic Diagnostics), and LOVD 3.0 (conflicting classifications). The variant was identified in control databases in 258 of 280002 chromosomes (1 homozygous) at a frequency of 0.0009214 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 215 of 127098 chromosomes (freq: 0.001692), Other in 5 of 7168 chromosomes (freq: 0.000698), European (Finnish) in 14 of 25108 chromosomes (freq: 0.000558), African in 10 of 24562 chromosomes (freq: 0.000407), Latino in 10 of 35374 chromosomes (freq: 0.000283) and South Asian in 4 of 30562 chromosomes (freq: 0.000131), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	This variant is associated with the following publications: (PMID: 23591405, 26878454) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the USH1G protein (p.Leu420Val). This variant is present in population databases (rs139897506, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with USH1G-related conditions. ClinVar contains an entry for this variant (Variation ID: 48126). 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 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Leu420Val var iant in USH1G has now been identified in 2 individuals with Usher syndrome and 5 individuals with hearing loss. One of the individuals with Usher syndrome had t wo pathogenic variants in another gene which explained the disease (Glockle 2014 ). A variant affecting the remaining copy of USH1G was not detected in any of th e other individuals (LMM data). This variant has been identified in 0.2% (109/62 876) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs139897506). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. Computational prediction tools and conservation analyses do not provi de strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Leu420Val variant is uncertain, these data sugge st that it is more likely to be benign. -

Usher syndrome type 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. -

USH1G-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.59
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.87
gMVP		0.52

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: rs139897506; hg19: chr17-72915673; COSMIC: COSV105876150; COSMIC: COSV105876150;