rs111033381

Variant names:

• chr1-215674614-C-A
• rs111033381
• NM_206933.4:c.13297G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):​c.13297G>T​(p.Val4433Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,614,142 control chromosomes in the GnomAD database, including 472 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V4433V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.27
• Publications: 17 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023987293).
• BP6: Variant 1-215674614-C-A is Benign according to our data. Variant chr1-215674614-C-A is described in ClinVar as Benign. ClinVar VariationId is 48415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0182 (2775/152280) while in subpopulation NFE AF = 0.0244 (1660/68022). AF 95% confidence interval is 0.0234. There are 46 homozygotes in GnomAd4. There are 1397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR gene

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.13297G>T	p.Val4433Leu	missense	Exon 63 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.13297G>T	p.Val4433Leu	missense	Exon 63 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.13297G>T	p.Val4433Leu	missense	Exon 63 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2775 AN: 152162 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0191 AC: 4802 AN: 250872 AF XY: 0.0188

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0219 AC: 32020 AN: 1461862 Hom.: 426 Cov.: 31 AF XY: 0.0212 AC XY: 15446 AN XY: 727226

African (AFR) AF: 0.00290 AC: 97 AN: 33480

American (AMR) AF: 0.00602 AC: 269 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 759 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00278 AC: 240 AN: 86258

European-Finnish (FIN) AF: 0.0481 AC: 2570 AN: 53418

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5768

European-Non Finnish (NFE) AF: 0.0239 AC: 26607 AN: 1112000

Other (OTH) AF: 0.0229 AC: 1386 AN: 60394

GnomAD4 genome AF: 0.0182 AC: 2775 AN: 152280 Hom.: 46 Cov.: 32 AF XY: 0.0188 AC XY: 1397 AN XY: 74460

African (AFR) AF: 0.00346 AC: 144 AN: 41560

American (AMR) AF: 0.0117 AC: 179 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0244 AC: 1660 AN: 68022

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0226 Hom.: 134

Bravo AF: 0.0157

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0192 AC: 2330

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0220

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.3
DANN	Benign	0.91
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
PhyloP100		-1.3
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.055
Sift	Benign	0.32	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.39		Loss of catalytic residue at V4433 (P = 0.1009)
MPC		0.030
ClinPred		0.016	T
GERP RS		-0.13
Varity_R		0.040
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111033381; hg19: chr1-215847956; COSMIC: COSV56394744;