rs17079425

Variant names:

• chr3-46995075-G-A
• rs17079425
• NM_015175.3:c.1340G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-46995075-G-A
• chr3-46995075-G-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.1340G>A​(p.Arg447His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,558,994 control chromosomes in the GnomAD database, including 1,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R447C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (255 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1700 hom.)
• Consequence: NBEAL2 NM_015175.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.65
• Publications: 18 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 (MetaRNN=0.0018942952).
• BP6: Variant 3-46995075-G-A is Benign according to our data. Variant chr3-46995075-G-A is described in ClinVar as Benign. ClinVar VariationId is 260577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.1340G>A	p.Arg447His	missense_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.1340G>A	p.Arg447His	missense_variant	Exon 13 of 54	2	NM_015175.3	ENSP00000415034.2
NBEAL2	ENST00000651747.1	c.1238G>A	p.Arg413His	missense_variant	Exon 12 of 53			ENSP00000499216.1
NBEAL2	ENST00000416683.5	c.-248G>A		upstream_gene_variant		1		ENSP00000410405.1

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5756 AN: 152194 Hom.: 254 Cov.: 33

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0643 AC: 11686 AN: 181794 AF XY: 0.0566

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0280 AC: 39332 AN: 1406682 Hom.: 1700 Cov.: 32 AF XY: 0.0278 AC XY: 19256 AN XY: 693098

African (AFR) AF: 0.0337 AC: 1084 AN: 32130

American (AMR) AF: 0.205 AC: 7876 AN: 38412

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 1679 AN: 25360

East Asian (EAS) AF: 0.142 AC: 5206 AN: 36602

South Asian (SAS) AF: 0.0431 AC: 3469 AN: 80420

European-Finnish (FIN) AF: 0.0182 AC: 891 AN: 48906

Middle Eastern (MID) AF: 0.0429 AC: 244 AN: 5690

European-Non Finnish (NFE) AF: 0.0158 AC: 17028 AN: 1081128

Other (OTH) AF: 0.0320 AC: 1855 AN: 58034

GnomAD4 genome AF: 0.0379 AC: 5775 AN: 152312 Hom.: 255 Cov.: 33 AF XY: 0.0402 AC XY: 2992 AN XY: 74494

African (AFR) AF: 0.0333 AC: 1386 AN: 41566

American (AMR) AF: 0.119 AC: 1819 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3470

East Asian (EAS) AF: 0.131 AC: 681 AN: 5188

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4826

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0172 AC: 1171 AN: 68016

Other (OTH) AF: 0.0350 AC: 74 AN: 2112

Alfa AF: 0.0289 Hom.: 168

Bravo AF: 0.0481

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.0273 AC: 114

ESP6500EA AF: 0.0178 AC: 149

ExAC AF: 0.0433 AC: 5085

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.036
Sift	Benign	0.21	T
Polyphen		0.052	B
Vest4		0.025
MPC		0.24
ClinPred		0.011	T
GERP RS		1.8
PromoterAI		-0.0096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.030
gMVP		0.17
Mutation Taster		=99/1	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: rs17079425; hg19: chr3-47036565; COSMIC: COSV52757080; COSMIC: COSV52757080;