5-172683592-C-G

Variant names:

• chr5-172683592-C-G
• rs1417964947
• NM_001142651.3:c.751C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142651.3(NEURL1B):​c.751C>G​(p.Pro251Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,289,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: NEURL1B NM_001142651.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.810
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053267986).

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.751C>G	p.Pro251Ala	missense	Exon 3 of 5	NP_001136123.1	A8MQ27-1
	NEURL1B	NM_001308177.2		c.205C>G	p.Pro69Ala	missense	Exon 2 of 4	NP_001295106.1	A8MQ27-2
	NEURL1B	NM_001308178.2		c.578-2579C>G		intron	N/A	NP_001295107.1	A8MQ27-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEURL1B	ENST00000369800.6	TSL:1 MANE Select	c.751C>G	p.Pro251Ala	missense	Exon 3 of 5	ENSP00000358815.5	A8MQ27-1
	NEURL1B	ENST00000522853.5	TSL:1	c.205C>G	p.Pro69Ala	missense	Exon 2 of 4	ENSP00000430001.1	A8MQ27-2
	NEURL1B	ENST00000520919.5	TSL:1	c.578-2579C>G		intron	N/A	ENSP00000429797.1	A8MQ27-3

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149270 Hom.: 0 Cov.: 32

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: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1140098 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 553510

African (AFR) AF: 0.00 AC: 0 AN: 22176

American (AMR) AF: 0.00 AC: 0 AN: 8558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14734

East Asian (EAS) AF: 0.00 AC: 0 AN: 24178

South Asian (SAS) AF: 0.00 AC: 0 AN: 43204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3756

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 952290

Other (OTH) AF: 0.00 AC: 0 AN: 45132

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149370 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72918

African (AFR) AF: 0.00 AC: 0 AN: 41236

American (AMR) AF: 0.00 AC: 0 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67040

Other (OTH) AF: 0.00 AC: 0 AN: 2070

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.1
DANN	Benign	0.48
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.81
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	0.79	T
Polyphen		0.028	B
Vest4		0.21
MutPred		0.17		Loss of glycosylation at P251 (P = 0.013)
MVP		0.085
MPC		0.49
ClinPred		0.067	T
GERP RS		1.2
Varity_R		0.050
gMVP		0.39
Mutation Taster		=92/8	polymorphism

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: rs1417964947; hg19: chr5-172110595;