rs1387680840

Variant names:

• chr13-34942867-C-A
• rs1387680840
• NM_001385012.1:c.47C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-34942867-C-A
• chr13-34942867-C-T

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.47C>A​(p.Pro16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000794 in 1,259,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P16L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: NBEA NM_001385012.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.864
• 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=0.20594627).

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.47C>A	p.Pro16His	missense	Exon 1 of 59	NP_001371941.1	Q5T321
	NBEA	NM_001379245.1		c.47C>A	p.Pro16His	missense	Exon 1 of 58	NP_001366174.1
	NBEA	NM_015678.5		c.47C>A	p.Pro16His	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.47C>A	p.Pro16His	missense	Exon 1 of 59	ENSP00000369271.2	Q5T321
	NBEA	ENST00000400445.8	TSL:5	c.47C>A	p.Pro16His	missense	Exon 1 of 58	ENSP00000383295.3	Q8NFP9-1
	NBEA	ENST00000691351.1		c.47C>A	p.Pro16His	missense	Exon 1 of 22	ENSP00000509284.1	A0A8I5QKR6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.94e-7 AC: 1 AN: 1259060 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 614562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25198

American (AMR) AF: 0.00 AC: 0 AN: 21354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18432

East Asian (EAS) AF: 0.00 AC: 0 AN: 30770

South Asian (SAS) AF: 0.00 AC: 0 AN: 64438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3556

European-Non Finnish (NFE) AF: 9.95e-7 AC: 1 AN: 1004758

Other (OTH) AF: 0.00 AC: 0 AN: 52002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.86
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.56	P
Vest4		0.10
MutPred		0.24		Loss of loop (P = 0.0986)
MVP		0.24
MPC		1.0
ClinPred		0.90	D
GERP RS		3.8
Varity_R		0.39
gMVP		0.48
Mutation Taster		=88/12	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

dbSNP: rs1387680840; hg19: chr13-35517004;