Genetic Variant NEURL4:p.Ala1527Thr (chr17-7316233-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_032442.3(NEURL4):c.4579G>A(p.Ala1527Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,613,772 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 3 hom. )

Consequence

NEURL4
NM_032442.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.705

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034599602).

BP6

Variant 17-7316233-C-T is Benign according to our data. Variant chr17-7316233-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3390331.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL4	NM_032442.3 link	c.4579G>A	p.Ala1527Thr	missense_variant	Exon 29 of 29	ENST00000399464.7	NP_115818.2	Q96JN8-1
NEURL4	NM_001005408.2 link	c.4573G>A	p.Ala1525Thr	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.4579G>A	p.Ala1527Thr	missense_variant	Exon 29 of 29	1	NM_032442.3	ENSP00000382390.2		Q96JN8-1
ENSG00000261915	ENST00000575474.1 link	n.975+43G>A		intron_variant	Intron 8 of 18	5		ENSP00000468772.1		K7ESM1

Frequencies

GnomAD3 genomes

AF:

0.000914

AC:

139

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00971

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00114

AC:

284

AN:

249484

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00951

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000629

AC:

919

AN:

1461516

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

445

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00871

Gnomad4 NFE exome

AF:

0.000347

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000913

AC:

139

AN:

152256

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00971

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000481

AC:

ExAC

AF:

0.000976

AC:

118

EpiCase

AF:

0.000763

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEURL4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0085

.;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.89

.;L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.90

N;N;.

REVEL

Benign

0.036

Sift

Benign

0.21

T;T;.

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0070

B;B;.

Vest4

0.042

MVP

0.043

MPC

0.51

ClinPred

0.023

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.082

gMVP

0.23

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

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