3-47001748-C-T

Variant names:

• chr3-47001748-C-T
• rs12489851
• NM_015175.3:c.4704C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_015175.3(NBEAL2):​c.4704C>T​(p.Asn1568Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,894 control chromosomes in the GnomAD database, including 2,181 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (226 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1955 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.83
• Publications: 7 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 -17 ACMG points.

• BP6: Variant 3-47001748-C-T is Benign according to our data. Variant chr3-47001748-C-T is described in ClinVar as Benign. ClinVar VariationId is 260580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015175.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	NM_015175.3	MANE Select	c.4704C>T	p.Asn1568Asn	synonymous	Exon 30 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.4602C>T	p.Asn1534Asn	synonymous	Exon 29 of 53	NP_001352045.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.4704C>T	p.Asn1568Asn	synonymous	Exon 30 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.2565C>T	p.Asn855Asn	synonymous	Exon 16 of 40	ENSP00000410405.1
	NBEAL2	ENST00000651747.1		c.4602C>T	p.Asn1534Asn	synonymous	Exon 29 of 53	ENSP00000499216.1

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4621 AN: 152188 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0494

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0612 AC: 15251 AN: 249078 AF XY: 0.0538

Gnomad AFR exome AF: 0.00808

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0283 AC: 41363 AN: 1461588 Hom.: 1955 Cov.: 31 AF XY: 0.0280 AC XY: 20342 AN XY: 727064

African (AFR) AF: 0.00621 AC: 208 AN: 33480

American (AMR) AF: 0.214 AC: 9564 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 1615 AN: 26136

East Asian (EAS) AF: 0.143 AC: 5685 AN: 39700

South Asian (SAS) AF: 0.0421 AC: 3633 AN: 86258

European-Finnish (FIN) AF: 0.0183 AC: 974 AN: 53298

Middle Eastern (MID) AF: 0.0416 AC: 240 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17656 AN: 1111862

Other (OTH) AF: 0.0296 AC: 1788 AN: 60368

GnomAD4 genome AF: 0.0304 AC: 4629 AN: 152306 Hom.: 226 Cov.: 33 AF XY: 0.0331 AC XY: 2465 AN XY: 74456

African (AFR) AF: 0.00768 AC: 319 AN: 41556

American (AMR) AF: 0.117 AC: 1783 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3470

East Asian (EAS) AF: 0.131 AC: 680 AN: 5178

South Asian (SAS) AF: 0.0495 AC: 239 AN: 4832

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1163 AN: 68038

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0287 Hom.: 151

Bravo AF: 0.0397

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		-4.8
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs12489851; hg19: chr3-47043238; COSMIC: COSV52755552; COSMIC: COSV52755552;