rs145760682

Positions:

chr3-47001271-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015175.3(NBEAL2):c.4485-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,602,400 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0049 ( 27 hom. )

Consequence

NBEAL2
NM_015175.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003062

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.60

Variant links:

Genes affected

NBEAL2 (HGNC:31928): (neurobeachin like 2) The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis. Mutations in this gene are a cause of gray platelet syndrome. [provided by RefSeq, Dec 2011]

NBEAL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-47001271-C-T is Benign according to our data. Variant chr3-47001271-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435926.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00342 (520/152250) while in subpopulation AMR AF= 0.00595 (91/15300). AF 95% confidence interval is 0.00496. There are 3 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEAL2	NM_015175.3 linkuse as main transcript	c.4485-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000450053.8

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEAL2	ENST00000450053.8 linkuse as main transcript	c.4485-8C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_015175.3	P2	Q6ZNJ1-1
NBEAL2	ENST00000416683.5 linkuse as main transcript	c.2348-8C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
NBEAL2	ENST00000651747.1 linkuse as main transcript	c.4383-8C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				A2
NBEAL2	ENST00000475689.1 linkuse as main transcript	n.322C>T	non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00495

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00301

AC:

743

AN:

246782

Hom.:

AF XY:

0.00287

AC XY:

384

AN XY:

133994

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00378

Gnomad ASJ exome

AF:

0.00184

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.000701

Gnomad NFE exome

AF:

0.00480

Gnomad OTH exome

AF:

0.00367

GnomAD4 exome

AF:

0.00492

AC:

7131

AN:

1450150

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

3374

AN XY:

719052

show subpopulations

Gnomad4 AFR exome

AF:

0.000844

Gnomad4 AMR exome

AF:

0.00414

Gnomad4 ASJ exome

AF:

0.00166

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000604

Gnomad4 NFE exome

AF:

0.00591

Gnomad4 OTH exome

AF:

0.00504

GnomAD4 genome

AF:

0.00342

AC:

520

AN:

152250

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00495

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.00394

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2017

- -

NBEAL2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Gray platelet syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.36

DANN

Benign

0.42

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.096

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over