10-103571601-G-A

Position:

• chr10-103571601-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004210.5(NEURL1):​c.428G>A​(p.Cys143Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEURL1 NM_004210.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEURL1	NM_004210.5	c.428G>A	p.Cys143Tyr	missense_variant	3/6	ENST00000369780.9	NP_004201.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEURL1	ENST00000369780.9	c.428G>A	p.Cys143Tyr	missense_variant	3/6	1	NM_004210.5	ENSP00000358795.4
NEURL1	ENST00000437579.1	c.377G>A	p.Cys126Tyr	missense_variant	3/3	2		ENSP00000416709.1
NEURL1	ENST00000455386.1	c.203G>A	p.Cys68Tyr	missense_variant	3/3	2		ENSP00000387714.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2024

The c.428G>A (p.C143Y) alteration is located in exon 3 (coding exon 3) of the NEURL1 gene. This alteration results from a G to A substitution at nucleotide position 428, causing the cysteine (C) at amino acid position 143 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D;T;D
Sift4G	Uncertain	0.043	D;T;T
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.47		Gain of disorder (P = 0.076);.;.;
MVP		0.69
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-105331358;