NM_001142651.3:c.548A>G

Variant names:

• chr5-172670301-A-G
• rs1758098737
• NM_001142651.3:c.548A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142651.3(NEURL1B):​c.548A>G​(p.Tyr183Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000082 in 1,220,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: NEURL1B NM_001142651.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142651.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEURL1B	NM_001142651.3	MANE Select	c.548A>G	p.Tyr183Cys	missense	Exon 2 of 5	NP_001136123.1	A8MQ27-1
	NEURL1B	NM_001308178.2		c.548A>G	p.Tyr183Cys	missense	Exon 2 of 4	NP_001295107.1	A8MQ27-3
	NEURL1B	NM_001308177.2		c.32-13118A>G		intron	N/A	NP_001295106.1	A8MQ27-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEURL1B	ENST00000369800.6	TSL:1 MANE Select	c.548A>G	p.Tyr183Cys	missense	Exon 2 of 5	ENSP00000358815.5	A8MQ27-1
	NEURL1B	ENST00000520919.5	TSL:1	c.548A>G	p.Tyr183Cys	missense	Exon 2 of 4	ENSP00000429797.1	A8MQ27-3
	NEURL1B	ENST00000522853.5	TSL:1	c.32-13118A>G		intron	N/A	ENSP00000430001.1	A8MQ27-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.20e-7 AC: 1 AN: 1220040 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 588098

African (AFR) AF: 0.00 AC: 0 AN: 23748

American (AMR) AF: 0.00 AC: 0 AN: 10776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17256

East Asian (EAS) AF: 0.00 AC: 0 AN: 27512

South Asian (SAS) AF: 0.00 AC: 0 AN: 53420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998948

Other (OTH) AF: 0.00 AC: 0 AN: 50400

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.79		Loss of phosphorylation at Y183 (P = 0.0347)
MVP		0.58
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.93
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs1758098737; hg19: chr5-172097304; COSMIC: COSV108900412;