Genetic Variant NEURL1:p.His43Tyr (chr10-103570913-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004210.5(NEURL1):c.127C>T(p.His43Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,078 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NEURL1
NM_004210.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

Variant links:

Genes affected

NEURL1 (HGNC:7761): (neuralized E3 ubiquitin protein ligase 1) Predicted to enable translation factor activity, non-nucleic acid binding and ubiquitin protein ligase activity. Involved in negative regulation of Notch signaling pathway; negative regulation of cell population proliferation; and positive regulation of apoptotic process. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

NEURL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27764687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL1	NM_004210.5 link	c.127C>T	p.His43Tyr	missense_variant	Exon 2 of 6	ENST00000369780.9	NP_004201.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEURL1	ENST00000369780.9 link	c.127C>T	p.His43Tyr	missense_variant	Exon 2 of 6	1	NM_004210.5	ENSP00000358795.4	O76050-1
NEURL1	ENST00000437579.1 link	c.76C>T	p.His26Tyr	missense_variant	Exon 2 of 3	2		ENSP00000416709.1	X6RLA8
NEURL1	ENST00000455386 link	c.-99C>T		5_prime_UTR_variant	Exon 2 of 3	2		ENSP00000387714.1	X6RBV8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

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:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127C>T (p.H43Y) alteration is located in exon 2 (coding exon 2) of the NEURL1 gene. This alteration results from a C to T substitution at nucleotide position 127, causing the histidine (H) at amino acid position 43 to be replaced by a tyrosine (Y). 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

0.18

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.0070

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.087

T;T

Sift4G

Benign

0.26

T;T

Polyphen

1.0

D;.

Vest4

0.30

MutPred

0.19

Loss of disorder (P = 0.037);.;

MVP

0.50

MPC

2.0

ClinPred

0.99

GERP RS

4.6

Varity_R

0.43

gMVP

0.57

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