5-172670261-G-T

Position:

• chr5-172670261-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142651.3(NEURL1B):​c.508G>T​(p.Val170Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,238,812 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: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NEURL1B NM_001142651.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23332545).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEURL1B	NM_001142651.3	c.508G>T	p.Val170Leu	missense_variant	2/5	ENST00000369800.6	NP_001136123.1
NEURL1B	NM_001308178.2	c.508G>T	p.Val170Leu	missense_variant	2/4		NP_001295107.1
NEURL1B	NM_001308177.2	c.32-13158G>T		intron_variant			NP_001295106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEURL1B	ENST00000369800.6	c.508G>T	p.Val170Leu	missense_variant	2/5	1	NM_001142651.3	ENSP00000358815.5
NEURL1B	ENST00000520919.5	c.508G>T	p.Val170Leu	missense_variant	2/4	1		ENSP00000429797.1
NEURL1B	ENST00000522853.5	c.32-13158G>T		intron_variant		1		ENSP00000430001.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 17 AN: 1238812 Hom.: 0 Cov.: 31 AF XY: 0.0000150 AC XY: 9 AN XY: 598782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Nov 22, 2022

The c.508G>T (p.V170L) alteration is located in exon 2 (coding exon 2) of the NEURL1B gene. This alteration results from a G to T substitution at nucleotide position 508, causing the valine (V) at amino acid position 170 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.078
Sift	Benign	0.076	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.24	.;B
Vest4		0.14
MutPred		0.53		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.45
MPC		0.78
ClinPred		0.58	D
GERP RS		4.0
Varity_R		0.20
gMVP		0.25

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

Other links and lift over

dbSNP: rs1168097564; hg19: chr5-172097264; COSMIC: COSV63940773;