rs111033421

Variant names:

• chr1-216078144-C-T
• rs111033421
• NM_206933.4:c.5517G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_206933.4(USH2A):​c.5517G>A​(p.Val1839Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,613,710 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.403
• Publications: 0 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 1-216078144-C-T is Benign according to our data. Variant chr1-216078144-C-T is described in ClinVar as Benign. ClinVar VariationId is 48533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.403 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00433 (659/152246) while in subpopulation AFR AF = 0.0152 (632/41562). AF 95% confidence interval is 0.0142. There are 10 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.5517G>A	p.Val1839Val	synonymous	Exon 27 of 72	NP_996816.3
	USH2A-AS2	NR_125992.1		n.137-929C>T		intron	N/A
	USH2A-AS2	NR_125993.1		n.136+5544C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5517G>A	p.Val1839Val	synonymous	Exon 27 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.5517G>A	p.Val1839Val	synonymous	Exon 27 of 73	ENSP00000501296.1
	USH2A-AS2	ENST00000430890.5	TSL:2	n.79-929C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 658 AN: 152128 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00112 AC: 280 AN: 250714 AF XY: 0.000723

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1461464 Hom.: 4 Cov.: 32 AF XY: 0.000352 AC XY: 256 AN XY: 727020

African (AFR) AF: 0.0145 AC: 486 AN: 33450

American (AMR) AF: 0.000605 AC: 27 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111772

Other (OTH) AF: 0.000663 AC: 40 AN: 60372

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152246 Hom.: 10 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74424

African (AFR) AF: 0.0152 AC: 632 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00189 Hom.: 2

Bravo AF: 0.00466

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.8
DANN	Benign	0.84
PhyloP100		-0.40
Mutation Taster		=99/1	polymorphism

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: rs111033421; hg19: chr1-216251486;