Genetic Variant NEURL4:p.Cys1514Ser (chr17-7316271-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032442.3(NEURL4):c.4541G>C(p.Cys1514Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NEURL4
NM_032442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
NEURL4	NM_032442.3 link	c.4541G>C	p.Cys1514Ser	missense_variant	Exon 29 of 29	ENST00000399464.7	NP_115818.2	Q96JN8-1
NEURL4	NM_001005408.2 link	c.4535G>C	p.Cys1512Ser	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.4541G>C	p.Cys1514Ser	missense_variant	Exon 29 of 29	1	NM_032442.3	ENSP00000382390.2		Q96JN8-1
ENSG00000261915	ENST00000575474.1 link	n.975+5G>C		splice_region_variant, intron_variant	Intron 8 of 18	5		ENSP00000468772.1		K7ESM1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249420

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4541G>C (p.C1514S) alteration is located in exon 29 (coding exon 29) of the NEURL4 gene. This alteration results from a G to C substitution at nucleotide position 4541, causing the cysteine (C) at amino acid position 1514 to be replaced by a serine (S). 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

0.32

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

N;N;.

REVEL

Benign

0.25

Sift

Benign

0.045

D;D;.

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.75

MutPred

0.48

.;Gain of glycosylation at C1514 (P = 0.0103);.;

MVP

0.12

MPC

0.65

ClinPred

0.76

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.74

Position offset: 5

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