rs139636452

Variant names:

• chr3-25751206-C-A
• rs139636452
• NM_018297.4:c.550G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-25751206-C-A
• chr3-25751206-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The ENST00000280700.10(NGLY1):​c.550G>T​(p.Val184Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,612,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V184I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: NGLY1 ENST00000280700.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.661
• Publications: 4 publications found

Genes affected

NGLY1 (HGNC:17646): (N-glycanase 1) This gene encodes an enzyme that catalyzes hydrolysis of an N(4)-(acetyl-beta-D-glucosaminyl) asparagine residue to N-acetyl-beta-D-glucosaminylamine and a peptide containing an aspartate residue. The encoded enzyme may play a role in the proteasome-mediated degradation of misfolded glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

NGLY1 Gene-Disease associations (from GenCC):

• congenital disorder of deglycosylation 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• NGLY1-deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007426828).
• BP6: Variant 3-25751206-C-A is Benign according to our data. Variant chr3-25751206-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00169 (257/152158) while in subpopulation AFR AF = 0.00549 (228/41518). AF 95% confidence interval is 0.00491. There are 0 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000280700.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	NM_018297.4	MANE Select	c.550G>T	p.Val184Phe	missense	Exon 4 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.550G>T	p.Val184Phe	missense	Exon 4 of 12	NP_001138765.1
	NGLY1	NM_001145294.2		c.424G>T	p.Val142Phe	missense	Exon 4 of 12	NP_001138766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.550G>T	p.Val184Phe	missense	Exon 4 of 12	ENSP00000280700.5
	NGLY1	ENST00000428257.5	TSL:1	c.550G>T	p.Val184Phe	missense	Exon 4 of 12	ENSP00000387430.1
	NGLY1	ENST00000308710.9	TSL:1	c.541G>T	p.Val181Phe	missense	Exon 4 of 12	ENSP00000307980.5

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152042 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000509 AC: 127 AN: 249566 AF XY: 0.000341

Gnomad AFR exome AF: 0.00587

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1460544 Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 132 AN XY: 726558

African (AFR) AF: 0.00518 AC: 173 AN: 33424

American (AMR) AF: 0.000628 AC: 28 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111408

Other (OTH) AF: 0.000696 AC: 42 AN: 60330

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74382

African (AFR) AF: 0.00549 AC: 228 AN: 41518

American (AMR) AF: 0.000917 AC: 14 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000612 Hom.: 0

Bravo AF: 0.00189

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital disorder of deglycosylation (1)
-	-	1	NGLY1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.66
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.087
Sift	Benign	0.047	D
Sift4G	Benign	0.57	T
Polyphen		0.077	B
Vest4		0.36
MVP		0.14
MPC		0.045
ClinPred		0.0072	T
GERP RS		0.47
PromoterAI		-0.0017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.35
Mutation Taster		=88/12	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: rs139636452; hg19: chr3-25792697;