13-34942660-C-T

Variant names:

• chr13-34942660-C-T
• rs924269207
• NM_001385012.1:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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=-0.7).
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 255 AD gene.

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.-161C>T		5_prime_UTR	Exon 1 of 59	NP_001371941.1	Q5T321
	NBEA	NM_001379245.1		c.-161C>T		5_prime_UTR	Exon 1 of 58	NP_001366174.1
	NBEA	NM_015678.5		c.-161C>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.-161C>T		5_prime_UTR	Exon 1 of 59	ENSP00000369271.2	Q5T321
	NBEA	ENST00000400445.8	TSL:5	c.-161C>T		5_prime_UTR	Exon 1 of 58	ENSP00000383295.3	Q8NFP9-1
	NBEA	ENST00000691351.1		c.-161C>T		5_prime_UTR	Exon 1 of 22	ENSP00000509284.1	A0A8I5QKR6

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

African (AFR) AF: 0.000616 AC: 4 AN: 6492

American (AMR) AF: 0.000169 AC: 1 AN: 5910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7388

East Asian (EAS) AF: 0.00 AC: 0 AN: 18716

South Asian (SAS) AF: 0.00 AC: 0 AN: 3610

European-Finnish (FIN) AF: 0.000636 AC: 12 AN: 18868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1130

European-Non Finnish (NFE) AF: 0.00209 AC: 376 AN: 179958

Other (OTH) AF: 0.000877 AC: 13 AN: 14820

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

African (AFR) AF: 0.000410 AC: 17 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00207 AC: 140 AN: 67776

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00202

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		-0.13
PromoterAI		0.077	Neutral
Mutation Taster		=280/20	polymorphism

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

Other links and lift over

dbSNP: rs924269207; hg19: chr13-35516797;