rs387907113

Positions:

• chr3-46993986-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015175.3(NBEAL2):​c.1163T>C​(p.Leu388Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NBEAL2 NM_015175.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.33

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 3-46993986-T-C is Pathogenic according to our data. Variant chr3-46993986-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 31118.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.1163T>C	p.Leu388Pro	missense_variant	11/54	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.1163T>C	p.Leu388Pro	missense_variant	11/54	2	NM_015175.3	ENSP00000415034	P2
NBEAL2	ENST00000651747.1	c.1061T>C	p.Leu354Pro	missense_variant	10/53			ENSP00000499216	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459808 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gray platelet syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 17, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.88		Loss of helix (P = 0.0123);
MVP		0.95
MPC		0.97
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.82
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387907113; hg19: chr3-47035476;