chr1-215782813-G-C

Position:

• chr1-215782813-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):​c.10510C>G​(p.Pro3504Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,613,950 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3504L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (20 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.12

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 Benign. Variant got -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011390686).
• BP6: Variant 1-215782813-G-C is Benign according to our data. Variant chr1-215782813-G-C is described in ClinVar as [Benign]. Clinvar id is 178577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215782813-G-C is described in Lovd as [Likely_benign]. Variant chr1-215782813-G-C is described in Lovd as [Benign]. Variant chr1-215782813-G-C is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.10510C>G	p.Pro3504Ala	missense_variant	53/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.10510C>G	p.Pro3504Ala	missense_variant	53/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.10510C>G	p.Pro3504Ala	missense_variant	53/73

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152126 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00162 AC: 408 AN: 251208 Hom.: 9 AF XY: 0.00231 AC XY: 314 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00101 AC: 1482 AN: 1461706 Hom.: 20 Cov.: 31 AF XY: 0.00142 AC XY: 1034 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000340

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152244 Hom.: 3 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00196 AC: 238

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	This variant is associated with the following publications: (PMID: 22135276, 28281779, 25999674) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	USH2A: BP4, BS1, BS2 -

Usher syndrome type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2017	p.Pro3504Ala in Exon 53 of USH2A: This variant has been reported as a `likely ne utral? variant in an Usher syndrome study based on either its presence in an aff ected individual who carried two other causative variants or because it did not segregate with disease (Le Quesne Stabej 2012). It was also identified in 1/878 (0.12%) control chromosomes by the same study (Le Quesne Stabej 2012), and in 1. 1% (348/30782) of South Asian chromosomes including 8 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs200372118). Th e proline (Pro) residue at position 3504 is not conserved in several species mam mals, with rat and mouse having an alanine (Ala), and computational tools (amino acid biochemical properties, SIFT, PolyPhen-2, AlignGVGD) do not suggest an imp act to the protein. In summary, this variant is not expected to have clinical si gnificance based on the conservation and computational data, and its presence in the general population. -

Retinitis pigmentosa 39 Benign:1

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	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.049
Sift	Benign	0.37	T
Sift4G	Benign	0.17	T
Polyphen		0.13	B
Vest4		0.70
MVP		0.81
MPC		0.032
ClinPred		0.024	T
GERP RS		3.3
Varity_R		0.053
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200372118; hg19: chr1-215956155;