13-34942926-G-A

Variant names:

• chr13-34942926-G-A
• NM_001385012.1:c.106G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001385012.1(NBEA):​c.106G>A​(p.Gly36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,386,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NBEA NM_001385012.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

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]

NBEA Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without early-onset generalized epilepsy

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: STRONG Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08286893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385012.1. 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
	NBEA	NM_001385012.1	MANE Select	c.106G>A	p.Gly36Ser	missense	Exon 1 of 59	NP_001371941.1	Q5T321
	NBEA	NM_001379245.1		c.106G>A	p.Gly36Ser	missense	Exon 1 of 58	NP_001366174.1
	NBEA	NM_015678.5		c.106G>A	p.Gly36Ser	missense	Exon 1 of 58	NP_056493.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEA	ENST00000379939.7	TSL:5 MANE Select	c.106G>A	p.Gly36Ser	missense	Exon 1 of 59	ENSP00000369271.2	Q5T321
	NBEA	ENST00000400445.8	TSL:5	c.106G>A	p.Gly36Ser	missense	Exon 1 of 58	ENSP00000383295.3	Q8NFP9-1
	NBEA	ENST00000691351.1		c.106G>A	p.Gly36Ser	missense	Exon 1 of 22	ENSP00000509284.1	A0A8I5QKR6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1386606 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683508

African (AFR) AF: 0.00 AC: 0 AN: 30116

American (AMR) AF: 0.00 AC: 0 AN: 37534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22762

East Asian (EAS) AF: 0.00 AC: 0 AN: 35260

South Asian (SAS) AF: 0.00 AC: 0 AN: 78312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1073840

Other (OTH) AF: 0.00 AC: 0 AN: 57204

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.090
Sift	Benign	0.34	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.23		Gain of glycosylation at G36 (P = 0.0016)
MVP		0.25
MPC		0.90
ClinPred		0.054	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.074
gMVP		0.65
Mutation Taster		=94/6	polymorphism

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

hg19: chr13-35517063;