rs111033439

Variant names:

• chr1-215782738-C-A
• rs111033439
• NM_206933.4:c.10585G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-215782738-C-A
• chr1-215782738-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_206933.4(USH2A):​c.10585G>T​(p.Gly3529Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,460,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3529S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.17
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215782738-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48353.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	Exon 53 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	Exon 53 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	Exon 53 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250880 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460910 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111612

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.74		Loss of stability (P = 0.1938);
MVP		0.97
MPC		0.24
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.91
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033439; hg19: chr1-215956080;