Genetic Variant NEURL4:p.Pro1535Ala (chr17-7316209-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032442.3(NEURL4):c.4603C>G(p.Pro1535Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NEURL4
NM_032442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.19

Publications

0 publications found

Variant links:

Genes affected

NEURL4 (HGNC:34410): (neuralized E3 ubiquitin protein ligase 4) The protein encoded by this gene is predicted and it includes two isoforms resulting from two alternatively spliced transcript variants. [provided by RefSeq, Jul 2008]

NEURL4 links:

ENSG00000261915 (HGNC:):

ENSG00000261915 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22272927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL4	NM_032442.3 link	c.4603C>G	p.Pro1535Ala	missense_variant	Exon 29 of 29	ENST00000399464.7	NP_115818.2	Q96JN8-1
NEURL4	NM_001005408.2 link	c.4597C>G	p.Pro1533Ala	missense_variant	Exon 29 of 29		NP_001005408.1	Q96JN8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEURL4	ENST00000399464.7 link	c.4603C>G	p.Pro1535Ala	missense_variant	Exon 29 of 29	1	NM_032442.3	ENSP00000382390.2		Q96JN8-1
ENSG00000261915	ENST00000575474.1 link	n.975+67C>G		intron_variant	Intron 8 of 18	5		ENSP00000468772.1		K7ESM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249538

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459646

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110006

Other (OTH)

AF:

0.00

AC:

AN:

60318

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.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4603C>G (p.P1535A) alteration is located in exon 29 (coding exon 29) of the NEURL4 gene. This alteration results from a C to G substitution at nucleotide position 4603, causing the proline (P) at amino acid position 1535 to be replaced by an alanine (A). 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

0.064

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.017

.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.6

.;M;.

PhyloP100

8.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

N;N;.

REVEL

Benign

0.17

Sift

Benign

0.16

T;T;.

Sift4G

Benign

0.14

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.21

MutPred

0.35

.;Loss of glycosylation at P1535 (P = 0.0236);.;

MVP

0.24

MPC

0.52

ClinPred

0.57

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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17-7316209-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over