6-117675685-C-A

Position:

• chr6-117675685-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138459.5(NUS1):​c.15C>A​(p.Tyr5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUS1 NM_138459.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.242

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.983 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-117675685-C-A is Pathogenic according to our data. Variant chr6-117675685-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1386407.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUS1	NM_138459.5	c.15C>A	p.Tyr5*	stop_gained	1/5	ENST00000368494.4	NP_612468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUS1	ENST00000368494.4	c.15C>A	p.Tyr5*	stop_gained	1/5	1	NM_138459.5	ENSP00000357480.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation, type IAA Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2021

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with NUS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr5*) in the NUS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NUS1 are known to be pathogenic (PMID: 29100083). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.58	D
Vest4		0.098
GERP RS		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-117996848;