Genetic Variant UBAP1L:c.910-7G>A (chr15-65094583-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_001163692.2(UBAP1L):c.910-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,549,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

UBAP1L
NM_001163692.2 splice_region, intron

Scores

Splicing: ADA: 0.9967

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.941

Publications

2 publications found

Variant links:

Genes affected

UBAP1L (HGNC:40028): (ubiquitin associated protein 1 like) Predicted to enable ubiquitin binding activity. Predicted to be involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway. Predicted to be part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

UBAP1L Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
retinal degeneration
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

UBAP1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-65094583-C-T is Pathogenic according to our data. Variant chr15-65094583-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3341500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163692.2. 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
	UBAP1L	NM_001163692.2	MANE Select	c.910-7G>A		splice_region intron	N/A	NP_001157164.1	F5GYI3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UBAP1L	ENST00000559089.6	TSL:1 MANE Select	c.910-7G>A	splice_region intron	N/A	ENSP00000454012.1	F5GYI3
UBAP1L	ENST00000561387.1	TSL:1	n.7046G>A	non_coding_transcript_exon	Exon 1 of 2
UBAP1L	ENST00000907325.1		c.910-7G>A	splice_region intron	N/A	ENSP00000577384.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000209

AC:

AN:

152796

AF XY:

0.000173

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000111

AC:

155

AN:

1397662

Hom.:

Cov.:

AF XY:

0.0000972

AC XY:

AN XY:

689410

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31568

American (AMR)

AF:

0.000392

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.00179

AC:

AN:

25176

East Asian (EAS)

AF:

0.000140

AC:

AN:

35732

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48820

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1077820

Other (OTH)

AF:

0.000362

AC:

AN:

57964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.000164

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41540

American (AMR)

AF:

0.000720

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000246

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinal dystrophy (1)

Tooth agenesis, selective, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

-0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -2

DS_AL_spliceai

0.89

Position offset: -7

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over