1-215741541-GAA-GA

Variant names:

• chr1-215741541-GA-G
• rs34565443
• NM_206933.4:c.11549-5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):​c.11549-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,117,120 control chromosomes in the GnomAD database, including 134 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.017 (114 hom.)
• Consequence: USH2A NM_206933.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.396
• 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 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-215741541-GA-G is Benign according to our data. Variant chr1-215741541-GA-G is described in ClinVar as Benign. ClinVar VariationId is 177774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0102 (1414/138782) while in subpopulation AMR AF = 0.0416 (580/13952). AF 95% confidence interval is 0.0388. There are 20 homozygotes in GnomAd4. There are 737 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.11549-5delT		splice_region intron	N/A	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.11549-5delT		splice_region intron	N/A	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.11549-5delT		splice_region intron	N/A	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1405 AN: 138720 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.000775

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0520 AC: 6144 AN: 118084 AF XY: 0.0486

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0674

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0171 AC: 16767 AN: 978338 Hom.: 114 Cov.: 33 AF XY: 0.0176 AC XY: 8548 AN XY: 485518

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0254 AC: 551 AN: 21704

American (AMR) AF: 0.120 AC: 3540 AN: 29458

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 273 AN: 15984

East Asian (EAS) AF: 0.0388 AC: 1002 AN: 25812

South Asian (SAS) AF: 0.0464 AC: 2553 AN: 55048

European-Finnish (FIN) AF: 0.0172 AC: 588 AN: 34236

Middle Eastern (MID) AF: 0.0204 AC: 87 AN: 4262

European-Non Finnish (NFE) AF: 0.00966 AC: 7267 AN: 752256

Other (OTH) AF: 0.0229 AC: 906 AN: 39578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0102 AC: 1414 AN: 138782 Hom.: 20 Cov.: 32 AF XY: 0.0110 AC XY: 737 AN XY: 66892

African (AFR) AF: 0.0109 AC: 413 AN: 37900

American (AMR) AF: 0.0416 AC: 580 AN: 13952

Ashkenazi Jewish (ASJ) AF: 0.000304 AC: 1 AN: 3286

East Asian (EAS) AF: 0.0236 AC: 113 AN: 4784

South Asian (SAS) AF: 0.0284 AC: 126 AN: 4440

European-Finnish (FIN) AF: 0.000775 AC: 6 AN: 7746

Middle Eastern (MID) AF: 0.0113 AC: 3 AN: 266

European-Non Finnish (NFE) AF: 0.00212 AC: 135 AN: 63664

Other (OTH) AF: 0.0195 AC: 37 AN: 1900

Alfa AF: 0.0247 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
PhyloP100		0.40
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34565443; hg19: chr1-215914883; COSMIC: COSV56377184;