NUS1 p.Arg290His

Variant names:

• chr6-117707002-G-A
• rs886037858
• NM_138459.5:c.869G>A
• NUS1 p.Arg290His

Your query was ambiguous. Multiple possible variants found:

• chr6-117707002-G-A
• chr6-117707002-GT-AC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PM5 PP3_Moderate PP5

The NM_138459.5(NUS1):​c.869G>A​(p.Arg290His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005204195: experimental evidence demonstrating decreased enzyme function in patient derived cells (Park_2014), as well as in an in vitro expression system (Grabinska_2017). PMID:25066056, 36672771, 28842490". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NUS1 NM_138459.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 8.71
• Publications: 12 publications found

Genes affected

NUS1 (HGNC:21042): (NUS1 dehydrodolichyl diphosphate synthase subunit) This gene encodes a type I single transmembrane domain receptor, which is a subunit of cis-prenyltransferase, and serves as a specific receptor for the neural and cardiovascular regulator Nogo-B. The encoded protein is essential for dolichol synthesis and protein glycosylation. This gene is highly expressed in non-small cell lung carcinomas as well as estrogen receptor-alpha positive breast cancer cells where it promotes epithelial mesenchymal transition. This gene is associated with the poor prognosis of human hepatocellular carcinoma patients. Naturally occurring mutations in this gene cause a congenital disorder of glycosylation and are associated with epilepsy. A knockout of the orthologous gene in mice causes embryonic lethality before day 6.5. Pseudogenes of this gene have been defined on chromosomes 13 and X. [provided by RefSeq, May 2017]

NUS1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 55, with seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital disorder of glycosylation, type IAA

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005204195: experimental evidence demonstrating decreased enzyme function in patient derived cells (Park_2014), as well as in an in vitro expression system (Grabinska_2017). PMID: 25066056, 36672771, 28842490
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-117707001-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1492830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 6-117707002-G-A is Pathogenic according to our data. Variant chr6-117707002-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253197.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138459.5. 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
	NUS1	NM_138459.5	MANE Select	c.869G>A	p.Arg290His	missense	Exon 5 of 5	NP_612468.1	Q96E22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUS1	ENST00000368494.4	TSL:1 MANE Select	c.869G>A	p.Arg290His	missense	Exon 5 of 5	ENSP00000357480.3	Q96E22
	NUS1	ENST00000885063.1		c.914G>A	p.Arg305His	missense	Exon 6 of 6	ENSP00000555122.1
	NUS1	ENST00000923852.1		c.593G>A	p.Arg198His	missense	Exon 3 of 3	ENSP00000593911.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250746 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460040 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726384

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.0000224 AC: 1 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110592

Other (OTH) AF: 0.0000166 AC: 1 AN: 60308

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Congenital disorder of glycosylation, type IAA (3)
1	-	-	Congenital disorder of glycosylation (1)
-	1	-	Intellectual disability, autosomal dominant 55, with seizures (1)
1	-	-	NUS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.95
gMVP		0.80
Mutation Taster		=4/96	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037858;

hg19: chr6-118028165;