chr3-47001271-C-T

Variant names:

• chr3-47001271-C-T
• rs145760682
• NM_015175.3:c.4485-8C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015175.3(NBEAL2):​c.4485-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,602,400 control chromosomes in the GnomAD database, including 30 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: NBEAL2 NM_015175.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003062
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.60
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-47001271-C-T is Benign according to our data. Variant chr3-47001271-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435926.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00342 (520/152250) while in subpopulation AMR AF = 0.00595 (91/15300). AF 95% confidence interval is 0.00496. There are 3 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.4485-8C>T		splice_region intron	N/A	NP_055990.1	Q6ZNJ1-1
	NBEAL2	NM_001365116.2		c.4383-8C>T		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.4485-8C>T		splice_region intron	N/A	ENSP00000415034.2	Q6ZNJ1-1
	NBEAL2	ENST00000416683.5	TSL:1	c.2346-8C>T		splice_region intron	N/A	ENSP00000410405.1	H0Y764
	NBEAL2	ENST00000651747.1		c.4383-8C>T		splice_region intron	N/A	ENSP00000499216.1	A0A494C1V1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152132 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00301 AC: 743 AN: 246782 AF XY: 0.00287

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00378

Gnomad ASJ exome AF: 0.00184

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000701

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00492 AC: 7131 AN: 1450150 Hom.: 27 Cov.: 32 AF XY: 0.00469 AC XY: 3374 AN XY: 719052

African (AFR) AF: 0.000844 AC: 28 AN: 33190

American (AMR) AF: 0.00414 AC: 183 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00166 AC: 43 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.000174 AC: 15 AN: 85998

European-Finnish (FIN) AF: 0.000604 AC: 32 AN: 52964

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5742

European-Non Finnish (NFE) AF: 0.00591 AC: 6520 AN: 1103030

Other (OTH) AF: 0.00504 AC: 301 AN: 59780

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152250 Hom.: 3 Cov.: 33 AF XY: 0.00306 AC XY: 228 AN XY: 74432

African (AFR) AF: 0.00156 AC: 65 AN: 41540

American (AMR) AF: 0.00595 AC: 91 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00495 AC: 337 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00410 Hom.: 2

Bravo AF: 0.00394

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Gray platelet syndrome (1)
-	-	1	NBEAL2-related disorder (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.42
PhyloP100		-1.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.096
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: rs145760682; hg19: chr3-47042761;