Genetic Variant USH2A:c.11549-6_11549-5dupTT (chr1-215741541-G-GAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_206933.4(USH2A):c.11549-6_11549-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,087,750 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USH2A
NM_206933.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.396

Publications

4 publications found

Variant links:

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

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11549-6_11549-5dupTT		splice_region_variant, intron_variant	Intron 59 of 71	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11549-5_11549-4insTT		splice_region_variant, intron_variant	Intron 59 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.11549-5_11549-4insTT		splice_region_variant, intron_variant	Intron 59 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

138820

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000271

AC:

AN:

118084

AF XY:

0.000253

show subpopulations

Gnomad AFR exome

AF:

0.000340

Gnomad AMR exome

AF:

0.000445

Gnomad ASJ exome

AF:

0.000289

Gnomad EAS exome

AF:

0.000228

Gnomad FIN exome

AF:

0.000296

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000388

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1087750

Hom.:

Cov.:

AF XY:

0.0000351

AC XY:

AN XY:

540740

show subpopulations

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

African (AFR)

AF:

0.000166

AC:

AN:

24108

American (AMR)

AF:

0.000404

AC:

AN:

32154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18362

East Asian (EAS)

AF:

0.0000342

AC:

AN:

29218

South Asian (SAS)

AF:

0.0000324

AC:

AN:

61822

European-Finnish (FIN)

AF:

0.0000777

AC:

AN:

38590

Middle Eastern (MID)

AF:

0.000216

AC:

AN:

4630

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

834536

Other (OTH)

AF:

0.0000451

AC:

AN:

44330

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

138820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

66874

African (AFR)

AF:

0.00

AC:

AN:

37844

American (AMR)

AF:

0.00

AC:

AN:

13942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3288

East Asian (EAS)

AF:

0.00

AC:

AN:

4806

South Asian (SAS)

AF:

0.00

AC:

AN:

4446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63700

Other (OTH)

AF:

0.00

AC:

AN:

1886

Alfa

AF:

0.000817

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

Splicing

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

Publications

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1-215741541-GAA-GAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over