rs794726683

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-47002750-TG-T
• chr3-47002750-TG-TGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_015175.3(NBEAL2):​c.5413delG​(p.Ala1805ArgfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,387,926 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: NBEAL2 NM_015175.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.5413delG	p.Ala1805ArgfsTer15	frameshift	Exon 33 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.5311delG	p.Ala1771ArgfsTer15	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.5413delG	p.Ala1805ArgfsTer15	frameshift	Exon 33 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.3274delG	p.Ala1092fs	frameshift	Exon 19 of 40	ENSP00000410405.1
	NBEAL2	ENST00000443829.5	TSL:1	c.517delG	p.Ala173fs	frameshift	Exon 3 of 23	ENSP00000414560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000432 AC: 6 AN: 1387926 Hom.: 0 Cov.: 66 AF XY: 0.00000727 AC XY: 5 AN XY: 688152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 24066

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

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82644

European-Finnish (FIN) AF: 0.0000749 AC: 3 AN: 40038

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

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073892

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000287833), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

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: rs794726683; hg19: chr3-47044240;