Genetic Variant NBEA:p.Ser40Gly (chr13-34942938-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001385012.1(NBEA):c.118A>G(p.Ser40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 144,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S40P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000083 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NBEA
NM_001385012.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.287

Publications

3 publications found

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 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

NBEA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04473853).

BP6

Variant 13-34942938-A-G is Benign according to our data. Variant chr13-34942938-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2523121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000828 (12/144938) while in subpopulation NFE AF = 0.000183 (12/65528). AF 95% confidence interval is 0.000105. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NBEA	NM_001385012.1	MANE Select	c.118A>G	p.Ser40Gly	missense	Exon 1 of 59	NP_001371941.1	Q5T321
NBEA	NM_001379245.1		c.118A>G	p.Ser40Gly	missense	Exon 1 of 58	NP_001366174.1
NBEA	NM_015678.5		c.118A>G	p.Ser40Gly	missense	Exon 1 of 58	NP_056493.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NBEA	ENST00000379939.7	TSL:5 MANE Select	c.118A>G	p.Ser40Gly	missense	Exon 1 of 59	ENSP00000369271.2	Q5T321
NBEA	ENST00000400445.8	TSL:5	c.118A>G	p.Ser40Gly	missense	Exon 1 of 58	ENSP00000383295.3	Q8NFP9-1
NBEA	ENST00000691351.1		c.118A>G	p.Ser40Gly	missense	Exon 1 of 22	ENSP00000509284.1	A0A8I5QKR6

Frequencies

GnomAD3 genomes

AF:

0.0000828

AC:

AN:

144938

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000183

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000408

AC:

AN:

196180

AF XY:

0.0000550

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000949

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000179

AC:

253

AN:

1416106

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

113

AN XY:

701018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30908

American (AMR)

AF:

0.00

AC:

AN:

41304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24010

East Asian (EAS)

AF:

0.00

AC:

AN:

36478

South Asian (SAS)

AF:

0.00

AC:

AN:

82372

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4386

European-Non Finnish (NFE)

AF:

0.000216

AC:

235

AN:

1088702

Other (OTH)

AF:

0.000309

AC:

AN:

58216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000828

AC:

AN:

144938

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

70740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38636

American (AMR)

AF:

0.00

AC:

AN:

14798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4892

South Asian (SAS)

AF:

0.00

AC:

AN:

4448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000183

AC:

AN:

65528

Other (OTH)

AF:

0.00

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000144

Hom.:

ExAC

AF:

0.0000420

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.052

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.60

M_CAP

Benign

0.056

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.29

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.22

REVEL

Benign

0.049

Sift

Benign

0.85

Sift4G

Benign

0.15

Polyphen

0.0010

Vest4

0.17

MutPred

0.23

Loss of glycosylation at S40 (P = 5e-04)

MVP

0.18

MPC

0.84

ClinPred

0.027

GERP RS

1.2

Varity_R

0.049

gMVP

0.56

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over