NM_001378026.1:c.518G>A

Variant names:

• chr2-203068395-G-A
• rs530440261
• NM_001378026.1:c.518G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001378026.1(NBEAL1):​c.518G>A​(p.Arg173Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,503,958 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NBEAL1 NM_001378026.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054441154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL1	NM_001378026.1	c.518G>A	p.Arg173Gln	missense_variant, splice_region_variant	Exon 7 of 56	ENST00000683969.1	NP_001364955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL1	ENST00000683969.1	c.518G>A	p.Arg173Gln	missense_variant, splice_region_variant	Exon 7 of 56		NM_001378026.1	ENSP00000508055.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151738 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 28 AN: 143700 AF XY: 0.000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000995

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.000758

GnomAD4 exome AF: 0.000163 AC: 220 AN: 1352220 Hom.: 0 Cov.: 26 AF XY: 0.000167 AC XY: 111 AN XY: 665816

African (AFR) AF: 0.00 AC: 0 AN: 30488

American (AMR) AF: 0.0000621 AC: 2 AN: 32206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24284

East Asian (EAS) AF: 0.0000575 AC: 2 AN: 34794

South Asian (SAS) AF: 0.00 AC: 0 AN: 70388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.000195 AC: 205 AN: 1050160

Other (OTH) AF: 0.000196 AC: 11 AN: 56010

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151738 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13 AN XY: 74066

African (AFR) AF: 0.0000484 AC: 2 AN: 41310

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.0000528 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518G>A (p.R173Q) alteration is located in exon 7 (coding exon 6) of the NBEAL1 gene. This alteration results from a G to A substitution at nucleotide position 518, causing the arginine (R) at amino acid position 173 to be replaced by a glutamine (Q). 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	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00072	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.083
Sift	Benign	0.57	T
Sift4G	Benign	0.17	T
Polyphen		0.068	B
Vest4		0.17
MVP		0.38
MPC		0.12
ClinPred		0.068	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.13
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs530440261; hg19: chr2-203933118; COSMIC: COSV71375223;