NM_015175.3:c.4783-24C>T

Variant names:

• chr3-47001896-C-T
• rs73075647
• NM_015175.3:c.4783-24C>T

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.4783-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,605,488 control chromosomes in the GnomAD database, including 28,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.17 (2296 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25798 hom.)
• Consequence: NBEAL2 NM_015175.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.847
• 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-47001896-C-T is Benign according to our data. Variant chr3-47001896-C-T is described in ClinVar as Benign. ClinVar VariationId is 260581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 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.4783-24C>T		intron	N/A	NP_055990.1
	NBEAL2	NM_001365116.2		c.4681-24C>T		intron	N/A	NP_001352045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.4783-24C>T		intron	N/A	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.2644-24C>T		intron	N/A	ENSP00000410405.1
	NBEAL2	ENST00000651747.1		c.4681-24C>T		intron	N/A	ENSP00000499216.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25504 AN: 152034 Hom.: 2293 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0972

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.152 AC: 37637 AN: 246880 AF XY: 0.155

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0860

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.183 AC: 265437 AN: 1453334 Hom.: 25798 Cov.: 34 AF XY: 0.181 AC XY: 130586 AN XY: 721212

African (AFR) AF: 0.148 AC: 4947 AN: 33378

American (AMR) AF: 0.0904 AC: 4031 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4641 AN: 26038

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39480

South Asian (SAS) AF: 0.0970 AC: 8358 AN: 86134

European-Finnish (FIN) AF: 0.174 AC: 9076 AN: 52118

Middle Eastern (MID) AF: 0.207 AC: 1191 AN: 5742

European-Non Finnish (NFE) AF: 0.202 AC: 222891 AN: 1105900

Other (OTH) AF: 0.172 AC: 10290 AN: 59966

GnomAD4 genome AF: 0.168 AC: 25502 AN: 152154 Hom.: 2296 Cov.: 33 AF XY: 0.163 AC XY: 12092 AN XY: 74394

African (AFR) AF: 0.149 AC: 6177 AN: 41522

American (AMR) AF: 0.126 AC: 1930 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 626 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0977 AC: 471 AN: 4822

European-Finnish (FIN) AF: 0.167 AC: 1772 AN: 10598

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13864 AN: 67952

Other (OTH) AF: 0.171 AC: 362 AN: 2112

Alfa AF: 0.188 Hom.: 873

Bravo AF: 0.162

Asia WGS AF: 0.0450 AC: 159 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.65
PhyloP100		0.85
BranchPoint Hunter		0.0
PromoterAI		-0.0060	Neutral
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)		0.0		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: rs73075647; hg19: chr3-47043386; COSMIC: COSV52756728; COSMIC: COSV52756728;