Variant 5-172683494-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142651.3(NEURL1B):c.653G>C(p.Ser218Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,501,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NEURL1B
NM_001142651.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

Variant links:

Genes affected

NEURL1B (HGNC:35422): (neuralized E3 ubiquitin protein ligase 1B) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent endocytosis. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

NEURL1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.110099286).

BS2

High AC in GnomAdExome4 at 177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NEURL1B	NM_001142651.3 linkuse as main transcript	c.653G>C	p.Ser218Thr	missense_variant	3/5	ENST00000369800.6	NP_001136123.1
NEURL1B	NM_001308177.2 linkuse as main transcript	c.107G>C	p.Ser36Thr	missense_variant	2/4		NP_001295106.1
NEURL1B	NM_001308178.2 linkuse as main transcript	c.578-2677G>C		intron_variant			NP_001295107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEURL1B	ENST00000369800.6 linkuse as main transcript	c.653G>C	p.Ser218Thr	missense_variant	3/5	1	NM_001142651.3	ENSP00000358815.5	A8MQ27-1
NEURL1B	ENST00000522853.5 linkuse as main transcript	c.107G>C	p.Ser36Thr	missense_variant	2/4	1		ENSP00000430001.1	A8MQ27-2
NEURL1B	ENST00000520919.5 linkuse as main transcript	c.578-2677G>C		intron_variant		1		ENSP00000429797.1	A8MQ27-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000389

AC:

AN:

102848

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

57382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000497

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:

0.0000770

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

177

AN:

1349622

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

665928

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000299

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.0000533

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000984

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.653G>C (p.S218T) alteration is located in exon 3 (coding exon 3) of the NEURL1B gene. This alteration results from a G to C substitution at nucleotide position 653, causing the serine (S) at amino acid position 218 to be replaced by a threonine (T). 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

0.084

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.011

.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

.;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.85

N;N

REVEL

Benign

0.079

Sift

Uncertain

0.016

D;T

Sift4G

Benign

0.33

T;T

Polyphen

0.92

.;P

Vest4

0.20

MutPred

0.28

.;Loss of relative solvent accessibility (P = 0.0306);

MVP

0.32

MPC

0.47

ClinPred

0.14

GERP RS

2.6

Varity_R

0.16

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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