chr3-47007703-A-G

Variant names:

• chr3-47007703-A-G
• rs74418680
• NM_015175.3:c.7507+6A>G

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.7507+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,608,668 control chromosomes in the GnomAD database, including 2,046 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (233 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1813 hom.)
• Consequence: NBEAL2 NM_015175.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005881
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.984
• 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=-0.81).
• BP6: Variant 3-47007703-A-G is Benign according to our data. Variant chr3-47007703-A-G is described in ClinVar as Benign. ClinVar VariationId is 260592.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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	NM_015175.3	MANE Select	c.7507+6A>G		splice_region intron	N/A	NP_055990.1	Q6ZNJ1-1
	NBEAL2	NM_001365116.2		c.7405+6A>G		splice_region intron	N/A	NP_001352045.1	A0A494C1V1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.7507+6A>G		splice_region intron	N/A	ENSP00000415034.2	Q6ZNJ1-1
	NBEAL2	ENST00000416683.5	TSL:1	c.5368+6A>G		splice_region intron	N/A	ENSP00000410405.1	H0Y764
	NBEAL2	ENST00000443829.5	TSL:1	c.2521+6A>G		splice_region intron	N/A	ENSP00000414560.1	H7C3Y7

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4744 AN: 152152 Hom.: 232 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0502

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0594 AC: 14434 AN: 242950 AF XY: 0.0523

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.0603

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0280 AC: 40731 AN: 1456398 Hom.: 1813 Cov.: 33 AF XY: 0.0277 AC XY: 20041 AN XY: 723848

African (AFR) AF: 0.00868 AC: 290 AN: 33410

American (AMR) AF: 0.208 AC: 9110 AN: 43766

Ashkenazi Jewish (ASJ) AF: 0.0613 AC: 1594 AN: 26012

East Asian (EAS) AF: 0.142 AC: 5618 AN: 39472

South Asian (SAS) AF: 0.0418 AC: 3584 AN: 85806

European-Finnish (FIN) AF: 0.0182 AC: 960 AN: 52862

Middle Eastern (MID) AF: 0.0412 AC: 237 AN: 5756

European-Non Finnish (NFE) AF: 0.0158 AC: 17535 AN: 1109144

Other (OTH) AF: 0.0300 AC: 1803 AN: 60170

GnomAD4 genome AF: 0.0313 AC: 4761 AN: 152270 Hom.: 233 Cov.: 33 AF XY: 0.0340 AC XY: 2533 AN XY: 74450

African (AFR) AF: 0.0105 AC: 436 AN: 41542

American (AMR) AF: 0.117 AC: 1790 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.132 AC: 683 AN: 5178

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4832

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0171 AC: 1163 AN: 68010

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0224 Hom.: 36

Bravo AF: 0.0407

Asia WGS AF: 0.0610 AC: 211 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Gray platelet syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.77
DANN	Benign	0.72
PhyloP100		-0.98
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.080		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: rs74418680; hg19: chr3-47049193; COSMIC: COSV52759241; COSMIC: COSV52759241;