chr3-47002750-T-TG

Variant names:

• chr3-47002750-T-TG
• rs794726683
• NM_015175.3:c.5413dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015175.3(NBEAL2):​c.5413dupG​(p.Ala1805GlyfsTer59) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,387,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NBEAL2 NM_015175.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.53
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-47002750-T-TG is Pathogenic according to our data. Variant chr3-47002750-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 31122.Status of the report is no_assertion_criteria_provided, 0 stars.

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.5413dupG	p.Ala1805GlyfsTer59	frameshift	Exon 33 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.5311dupG	p.Ala1771GlyfsTer59	frameshift	Exon 32 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.5413dupG	p.Ala1805GlyfsTer59	frameshift	Exon 33 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.3274dupG	p.Ala1092fs	frameshift	Exon 19 of 40	ENSP00000410405.1
	NBEAL2	ENST00000443829.5	TSL:1	c.517dupG	p.Ala173fs	frameshift	Exon 3 of 23	ENSP00000414560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000107 AC: 2 AN: 186074 AF XY: 0.00

Gnomad AFR exome AF: 0.000102

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1387934 Hom.: 0 Cov.: 66 AF XY: 0.00000436 AC XY: 3 AN XY: 688150

African (AFR) AF: 0.00 AC: 0 AN: 31852

American (AMR) AF: 0.00 AC: 0 AN: 38710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35124

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5054

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073896

Other (OTH) AF: 0.00 AC: 0 AN: 56546

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Gray platelet syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794726683; hg19: chr3-47044240;