Genetic Variant NEURL4:p.Met1418Val (chr17-7317527-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032442.3(NEURL4):c.4252A>G(p.Met1418Val) variant causes a missense change. The variant allele was found at a frequency of 0.00672 in 1,614,164 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 72 hom. )

Consequence

NEURL4
NM_032442.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.17

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062610805).

BP6

Variant 17-7317527-T-C is Benign according to our data. Variant chr17-7317527-T-C is described in ClinVar as [Benign]. Clinvar id is 771020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL4	NM_032442.3 link	c.4252A>G	p.Met1418Val	missense_variant	Exon 27 of 29	ENST00000399464.7	NP_115818.2	Q96JN8-1
NEURL4	NM_001005408.2 link	c.4246A>G	p.Met1416Val	missense_variant	Exon 27 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.4252A>G	p.Met1418Val	missense_variant	Exon 27 of 29	1	NM_032442.3	ENSP00000382390.2		Q96JN8-1
ENSG00000261915	ENST00000575474.1 link	n.691A>G		non_coding_transcript_exon_variant	Exon 6 of 19	5		ENSP00000468772.1		K7ESM1

Frequencies

GnomAD3 genomes

AF:

0.00458

AC:

697

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00518

AC:

1292

AN:

249564

Hom.:

AF XY:

0.00564

AC XY:

764

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0151

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00603

Gnomad OTH exome

AF:

0.00478

GnomAD4 exome

AF:

0.00694

AC:

10146

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

5156

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0137

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00755

Gnomad4 OTH exome

AF:

0.00594

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152298

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

329

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00995

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00703

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00577

Hom.:

Bravo

AF:

0.00474

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000733

AC:

ESP6500EA

AF:

0.00835

AC:

ExAC

AF:

0.00526

AC:

636

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00682

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.0059

.;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.050

.;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.49

N;N;.

REVEL

Benign

0.074

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.39

MVP

0.043

MPC

0.54

ClinPred

0.0074

GERP RS

3.8

Varity_R

0.13

gMVP

0.57

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