chr1-215648591-A-G

Position:

• chr1-215648591-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_206933.4(USH2A):​c.14519T>C​(p.Leu4840Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000396 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L4840L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:15
• Conservation: PhyloP100: 4.41

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.14519T>C	p.Leu4840Pro	missense_variant	66/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14519T>C	p.Leu4840Pro	missense_variant	66/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14519T>C	p.Leu4840Pro	missense_variant	66/73

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000306 AC: 77 AN: 251294 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135822

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000402 AC: 588 AN: 1461876 Hom.: 1 Cov.: 31 AF XY: 0.000408 AC XY: 297 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000441

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000471 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000654

EpiControl AF: 0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
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	GeneDx	Nov 16, 2022	Reported as homozygous variant in a patient with Usher syndrome, with another variant, C1900G, in cis on both alleles (Bonnet et al., 2016); Observed in a patient with retinitis pigmentosa in published literature (McGee et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24944099, 27460420, 20507924) -
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	Invitae	Oct 17, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4840 of the USH2A protein (p.Leu4840Pro). This variant is present in population databases (rs143275144, gnomAD 0.04%). This missense change has been observed in individual(s) with retinal disease (PMID: 20507924; Invitae). ClinVar contains an entry for this variant (Variation ID: 48442). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Usher syndrome type 2A Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 20, 2018	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 20, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Leu4840Pro variant in USH2A has been previously reported by our laboratory in 2 individuals with hearing loss who each carried different homozygous pathogenic variants in another gene that explained the hearing loss. This variant has also been reported in 3 individuals with either retinitis pigmentosa or Usher syndrome. It was homozygous in 1 individual, but a variant affecting the remaining copy of USH2A was not identified in the other 2 individuals (McGee 2010, Baux 2014, Bonnet 2016). It has also been identified in 0.05% (59/129026) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 48442) .The leucine (Leu) at position 4840 is not highly conserved in mammals and evolutionary distant species, and two mammals (prairie vole and Golden hamster) have a proline (Pro) at the position, supporting that this change at this position may be tolerated. In summary, while the clinical significance of the p.Leu4804Pro variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2_Supporting, PP4, PM3_Supporting, BP4. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 24, 2022

- -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, PP3_Supporting -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.96
MPC		0.10
ClinPred		0.16	T
GERP RS		5.6
Varity_R		0.59
gMVP		0.80

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: rs143275144; hg19: chr1-215821933;