ENST00000379939:c.-8G>T

Variant names:

• chr13-34942813-G-T
• rs1250943920
• NM_001385012.1:c.-8G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000379939.7(NBEA):​c.-8G>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 0.0000132 in 1,360,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NBEA ENST00000379939.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000124 (15/1208472) while in subpopulation SAS AF = 0.000198 (11/55534). AF 95% confidence interval is 0.000111. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379939.7. 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.-8G>T		5_prime_UTR	Exon 1 of 59	NP_001371941.1	Q5T321
	NBEA	NM_001379245.1		c.-8G>T		5_prime_UTR	Exon 1 of 58	NP_001366174.1
	NBEA	NM_015678.5		c.-8G>T		5_prime_UTR	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.-8G>T		5_prime_UTR	Exon 1 of 59	ENSP00000369271.2	Q5T321
	NBEA	ENST00000400445.8	TSL:5	c.-8G>T		5_prime_UTR	Exon 1 of 58	ENSP00000383295.3	Q8NFP9-1
	NBEA	ENST00000691351.1		c.-8G>T		5_prime_UTR	Exon 1 of 22	ENSP00000509284.1	A0A8I5QKR6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151444 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.0000124 AC: 15 AN: 1208472 Hom.: 0 Cov.: 27 AF XY: 0.0000154 AC XY: 9 AN XY: 585920

African (AFR) AF: 0.00 AC: 0 AN: 23230

American (AMR) AF: 0.0000833 AC: 1 AN: 12008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16760

East Asian (EAS) AF: 0.0000352 AC: 1 AN: 28386

South Asian (SAS) AF: 0.000198 AC: 11 AN: 55534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3378

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989134

Other (OTH) AF: 0.0000401 AC: 2 AN: 49818

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151552 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74054

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5028

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67676

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.74
PhyloP100		-0.0020

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: rs1250943920; hg19: chr13-35516950;