rs3816531

Variant names:

• chr3-47006072-T-C
• rs3816531
• NM_015175.3:c.6919+9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015175.3(NBEAL2):​c.6919+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 1,613,270 control chromosomes in the GnomAD database, including 2,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (357 hom., cov: 33)
  • Exomes 𝑓: 0.030 (2081 hom.)
• Consequence: NBEAL2 NM_015175.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.31
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• gray platelet syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-47006072-T-C is Benign according to our data. Variant chr3-47006072-T-C is described in ClinVar as Benign. ClinVar VariationId is 260591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.6919+9T>C		intron_variant	Intron 43 of 53	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.6919+9T>C		intron_variant	Intron 43 of 53	2	NM_015175.3	ENSP00000415034.2

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7612 AN: 152150 Hom.: 353 Cov.: 33

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0663 AC: 16481 AN: 248612 AF XY: 0.0575

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.0653

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0304 AC: 44346 AN: 1461002 Hom.: 2081 Cov.: 34 AF XY: 0.0297 AC XY: 21583 AN XY: 726742

African (AFR) AF: 0.0767 AC: 2567 AN: 33468

American (AMR) AF: 0.217 AC: 9700 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0661 AC: 1727 AN: 26126

East Asian (EAS) AF: 0.143 AC: 5695 AN: 39690

South Asian (SAS) AF: 0.0421 AC: 3632 AN: 86248

European-Finnish (FIN) AF: 0.0182 AC: 968 AN: 53118

Middle Eastern (MID) AF: 0.0428 AC: 247 AN: 5768

European-Non Finnish (NFE) AF: 0.0160 AC: 17754 AN: 1111524

Other (OTH) AF: 0.0341 AC: 2056 AN: 60350

GnomAD4 genome AF: 0.0501 AC: 7633 AN: 152268 Hom.: 357 Cov.: 33 AF XY: 0.0519 AC XY: 3861 AN XY: 74452

African (AFR) AF: 0.0761 AC: 3164 AN: 41552

American (AMR) AF: 0.123 AC: 1876 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3468

East Asian (EAS) AF: 0.132 AC: 683 AN: 5184

South Asian (SAS) AF: 0.0506 AC: 244 AN: 4822

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1178 AN: 68010

Other (OTH) AF: 0.0435 AC: 92 AN: 2116

Alfa AF: 0.0382 Hom.: 97

Bravo AF: 0.0622

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gray platelet syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.13
DANN	Benign	0.73
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3816531; hg19: chr3-47047562; COSMIC: COSV52757124; COSMIC: COSV52757124;