13-34942660-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001385012.1(NBEA):c.-161C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 408,456 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: NBEA NM_001385012.1 5_prime_UTR
• Scores: Splicing: ADA: 0.002176
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.129

Genes affected

NBEA (HGNC:7648): (neurobeachin) This gene encodes a member of a large, diverse group of A-kinase anchor proteins that target the activity of protein kinase A to specific subcellular sites by binding to its type II regulatory subunits. Brain-specific expression and coat protein-like membrane recruitment of a highly similar protein in mouse suggest an involvement in neuronal post-Golgi membrane traffic. Mutations in this gene may be associated with a form of autism. This gene and its expression are frequently disrupted in patients with multiple myeloma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants may exist, but their full-length nature has not been determined.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00168 (255/151564) while in subpopulation NFE AF= 0.00207 (140/67776). AF 95% confidence interval is 0.00179. There are 4 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEA	NM_001385012.1	c.-161C>T		5_prime_UTR_variant	1/59	ENST00000379939.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEA	ENST00000379939.7	c.-161C>T		5_prime_UTR_variant	1/59	5	NM_001385012.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 151458 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00158 AC: 406 AN: 256892 Hom.: 0 Cov.: 5 AF XY: 0.00145 AC XY: 188 AN XY: 129880

Gnomad4 AFR exome AF: 0.000616

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000636

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.000877

GnomAD4 genome AF: 0.00168 AC: 255 AN: 151564 Hom.: 4 Cov.: 31 AF XY: 0.00136 AC XY: 101 AN XY: 74098

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.054
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: rs924269207; hg19: chr13-35516797;