3-46992480-C-T

Variant names:

• chr3-46992480-C-T
• rs201015016
• NM_015175.3:c.1038C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015175.3(NBEAL2):​c.1038C>T​(p.Tyr346Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,605,408 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.12
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-46992480-C-T is Benign according to our data. Variant chr3-46992480-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00193 (294/152116) while in subpopulation NFE AF = 0.00328 (223/67980). AF 95% confidence interval is 0.00293. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.1038C>T	p.Tyr346Tyr	synonymous	Exon 10 of 54	NP_055990.1	Q6ZNJ1-1
	NBEAL2	NM_001365116.2		c.1011+534C>T		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.1038C>T	p.Tyr346Tyr	synonymous	Exon 10 of 54	ENSP00000415034.2	Q6ZNJ1-1
	NBEAL2	ENST00000651747.1		c.1011+534C>T		intron	N/A	ENSP00000499216.1	A0A494C1V1
	NBEAL2	ENST00000933460.1		c.1032+534C>T		intron	N/A	ENSP00000603519.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 151998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00191 AC: 446 AN: 233492 AF XY: 0.00183

Gnomad AFR exome AF: 0.000523

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000533

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00263 AC: 3822 AN: 1453292 Hom.: 7 Cov.: 32 AF XY: 0.00254 AC XY: 1834 AN XY: 722144

African (AFR) AF: 0.000603 AC: 20 AN: 33184

American (AMR) AF: 0.00153 AC: 67 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 37 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84416

European-Finnish (FIN) AF: 0.000706 AC: 37 AN: 52406

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.00317 AC: 3513 AN: 1108552

Other (OTH) AF: 0.00241 AC: 145 AN: 60048

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152116 Hom.: 1 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74380

African (AFR) AF: 0.000531 AC: 22 AN: 41460

American (AMR) AF: 0.00229 AC: 35 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 67980

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Gray platelet syndrome (1)
-	-	1	NBEAL2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.80
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs201015016; hg19: chr3-47033970;