rs146445078

chr1-215844349-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_206933.4(USH2A):c.9203T>C(p.Val3068Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. V3068M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.494

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020991892).
• BP6: Variant 1-215844349-A-G is Benign according to our data. Variant chr1-215844349-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48614.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9203T>C	p.Val3068Ala	missense_variant	46/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9203T>C	p.Val3068Ala	missense_variant	46/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9203T>C	p.Val3068Ala	missense_variant	46/73

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.000661

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000411 AC: 103 AN: 250692 Hom.: 0 AF XY: 0.000391 AC XY: 53 AN XY: 135468

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000724

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000579 AC: 846 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.000568 AC XY: 413 AN XY: 727040

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.000694

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74490

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000718 Hom.: 0

Bravo AF: 0.000597

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	Reported in an individual with hearing loss who also harbored a nonsense variant on the same USH2A allele (in cis), however, this individual did not have an additional disease-causing variant on the opposite allele (in trans) (Tang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25991456, 32707200, 32483926) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 01, 2021

NM_206933.2(USH2A):c.9203T>C(V3068A) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. V3068A has been observed in cases with relevant disease (PMID: 25991456). Functional assessments of this variant are not available in the literature. V3068A has been observed in population frequency databases (gnomAD: NFE 0.07%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.9203T>C(V3068A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2017

p.Val3068Ala in exon 46 of USH2A: This variant is not expected to have clinical significance because of a lack of conservation across species including mammals. Of note, rat, mouse and opossum have an alanine at this position despite high n earby amino acid conservation. It has been identified in 85/126144 of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs146445078). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	13
Dann	Benign	0.76
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.066
Sift	Benign	0.83	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.26
MVP		0.69
MPC		0.034
ClinPred		0.0061	T
GERP RS		3.7
Varity_R		0.030
gMVP		0.22

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: rs146445078; hg19: chr1-216017691;