chr13-34942878-A-C

Position:

chr13-34942878-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_001385012.1(NBEA):c.58A>C(p.Ile20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,432,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NBEA
NM_001385012.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0310

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NBEA. . Gene score misZ 5.5108 (greater than the threshold 3.09). Trascript score misZ 5.4439 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, neurodevelopmental disorder with or without early-onset generalized epilepsy, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050911307).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000249 (32/1284220) while in subpopulation SAS AF= 0.000253 (17/67300). AF 95% confidence interval is 0.00016. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBEA	NM_001385012.1 linkuse as main transcript	c.58A>C	p.Ile20Leu	missense_variant	1/59	ENST00000379939.7	NP_001371941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBEA	ENST00000379939.7 linkuse as main transcript	c.58A>C	p.Ile20Leu	missense_variant	1/59	5	NM_001385012.1	ENSP00000369271.2		Q5T321

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000219

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

71930

Hom.:

AF XY:

0.0000785

AC XY:

AN XY:

38198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000249

AC:

AN:

1284220

Hom.:

Cov.:

AF XY:

0.0000366

AC XY:

AN XY:

627912

show subpopulations

Gnomad4 AFR exome

AF:

0.0000376

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000253

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000128

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72126

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000219

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2024

The c.58A>C (p.I20L) alteration is located in exon 1 (coding exon 1) of the NBEA gene. This alteration results from a A to C substitution at nucleotide position 58, causing the isoleucine (I) at amino acid position 20 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.37

DEOGEN2

Benign

0.063

T;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.60

T;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0051

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;.;.;.

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-0.11

N;N;.;N

REVEL

Benign

0.086

Sift

Benign

0.88

T;T;.;T

Sift4G

Benign

0.64

T;T;T;T

Polyphen

0.0010

.;.;.;B

Vest4

0.087

MutPred

0.25

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.29

MPC

0.90

ClinPred

0.018

GERP RS

-1.2

Varity_R

0.10

gMVP

0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over