Genetic Variant NM_001378026.1:c.57T>A (chr2-203041770-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378026.1(NBEAL1):c.57T>A(p.Asp19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NBEAL1
NM_001378026.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Publications

0 publications found

Variant links:

Genes affected

NBEAL1 (HGNC:20681): (neurobeachin like 1) Predicted to enable protein kinase binding activity. Predicted to be involved in protein localization. Predicted to be active in cytosol and membrane. [provided by Alliance of Genome Resources, Apr 2022]

NBEAL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL1	NM_001378026.1 link	c.57T>A	p.Asp19Glu	missense_variant	Exon 3 of 56	ENST00000683969.1	NP_001364955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL1	ENST00000683969.1 link	c.57T>A	p.Asp19Glu	missense_variant	Exon 3 of 56		NM_001378026.1	ENSP00000508055.1		A0A804HKS6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31778

American (AMR)

AF:

0.00

AC:

AN:

35612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

36278

South Asian (SAS)

AF:

0.00

AC:

AN:

79300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1078018

Other (OTH)

AF:

0.00

AC:

AN:

57966

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.57T>A (p.D19E) alteration is located in exon 3 (coding exon 2) of the NBEAL1 gene. This alteration results from a T to A substitution at nucleotide position 57, causing the aspartic acid (D) at amino acid position 19 to be replaced by a glutamic acid (E). 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

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0069

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.3

PhyloP100

1.8

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.29

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.61

MutPred

0.49

Loss of helix (P = 0.028);

MVP

0.61

MPC

0.52

ClinPred

0.95

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.32

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over