rs368675850

Variant names:

• chr1-215728383-G-A
• rs368675850
• NM_206933.4:c.11713C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-215728383-G-A
• chr1-215728383-G-T

Variant summary

Our verdict is Pathogenic. The variant received 5 ACMG points: 5P and 0B. PP3 PP4 PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The c.11713C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3905 (p.Arg3905Cys). The highest population minor allele frequency in gnomAD v4 is 0.007% (6/75036) in the African / African American population, which meets the ClinGen Hearing Loss VCEP threshold (≤0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 6 individuals with Usher syndrome and at least 4 individuals with inherited retinal dystrophy. Of those individuals, 1 was homozygous and 7 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. At least 1 of those were confirmed in trans by family testing (PM3_VeryStrong, PMID:31877679, 25333064, 28559085, 24944099, 34781295, 36011402, 32531858, 36909829, 27208204, 37217489). At least one patient with this variant was diagnosed with Usher syndrome, which is highly specific for USH2A-related disorders (PP4, PMID:31877679). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1393629/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: USH2A NM_206933.4 missense, splice_region
• Scores: Splicing: ADA: 0.9728
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:3
• Conservation: PhyloP100: 7.65
• Publications: 5 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 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Pathogenic. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.11713C>T	p.Arg3905Cys	missense splice_region	Exon 61 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.11713C>T	p.Arg3905Cys	missense splice_region	Exon 61 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.11713C>T	p.Arg3905Cys	missense splice_region	Exon 61 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 247752 AF XY: 0.0000223

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461572 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727086

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000448 AC: 2 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111950

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74478

African (AFR) AF: 0.000120 AC: 5 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	not provided (4)
2	1	-	Retinal dystrophy (3)
2	-	-	Usher syndrome (2)
1	1	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (2)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Retinitis pigmentosa 39 (1)
1	-	-	USH2A-related disorder (1)
1	-	-	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.6
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.97
MPC		0.19
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.47
gMVP		0.70
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.86
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

Other links and lift over

dbSNP: rs368675850; hg19: chr1-215901725;