rs147883884

Positions:

chr1-216070109-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_206933.4(USH2A):c.6041A>C(p.Asn2014Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,613,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2014K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.414

Variant links:

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008790642).

BP6

Variant 1-216070109-T-G is Benign according to our data. Variant chr1-216070109-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 48549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216070109-T-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6041A>C	p.Asn2014Thr	missense_variant	30/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.6041A>C	p.Asn2014Thr	missense_variant	30/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6041A>C	p.Asn2014Thr	missense_variant	30/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00900

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000689

AC:

173

AN:

251182

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.0100

Gnomad AMR exome

AF:

0.000116

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:

0.0000176

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000231

AC:

338

AN:

1461650

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00911

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.00251

AC:

383

AN:

152286

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00902

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000464

Hom.:

Bravo

AF:

0.00291

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000906

AC:

110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 11, 2012	This variant is not expected to have clinical significance because it has been i dentified in 23/4552 (0.5%) control chromosomes from a broad, though clinically and racially unspecified population (dbSNP rs147883884) and the variant occurs a t an amino acid position that is poorly conserved with Thr present in most mamma ls. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.6

DANN

Benign

0.68

DEOGEN2

Benign

0.024

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.055

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.83

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.65

REVEL

Benign

0.059

Sift

Benign

1.0

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.19

MVP

0.62

MPC

0.030

ClinPred

0.0042

GERP RS

0.41

Varity_R

0.038

gMVP

0.20

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