rs115611407

Variant names:

• chr3-46995088-G-A
• rs115611407
• NM_015175.3:c.1353G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-46995088-G-A
• chr3-46995088-G-C
• chr3-46995088-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015175.3(NBEAL2):​c.1353G>A​(p.Pro451Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,567,158 control chromosomes in the GnomAD database, including 1,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (232 hom., cov: 33)
  • Exomes 𝑓: 0.027 (1683 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.77

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-46995088-G-A is Benign according to our data. Variant chr3-46995088-G-A is described in ClinVar as [Benign]. Clinvar id is 260578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.1353G>A	p.Pro451Pro	synonymous_variant	Exon 13 of 54	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.1353G>A	p.Pro451Pro	synonymous_variant	Exon 13 of 54	2	NM_015175.3	ENSP00000415034.2
NBEAL2	ENST00000651747.1	c.1251G>A	p.Pro417Pro	synonymous_variant	Exon 12 of 53			ENSP00000499216.1
NBEAL2	ENST00000416683.5	c.-235G>A		upstream_gene_variant		1		ENSP00000410405.1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4739 AN: 152226 Hom.: 231 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0623 AC: 11672 AN: 187312 Hom.: 959 AF XY: 0.0547 AC XY: 5564 AN XY: 101646

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.0624

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.0432

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0272 AC: 38427 AN: 1414814 Hom.: 1683 Cov.: 32 AF XY: 0.0270 AC XY: 18863 AN XY: 698542

Gnomad4 AFR exome AF: 0.00878

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0312 AC: 4754 AN: 152344 Hom.: 232 Cov.: 33 AF XY: 0.0339 AC XY: 2527 AN XY: 74498

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0616

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0499

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0167 Hom.: 23

Bravo AF: 0.0406

Asia WGS AF: 0.0590 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gray platelet syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs115611407; hg19: chr3-47036578; COSMIC: COSV52757093; COSMIC: COSV52757093;