chr6-117675698-C-G

Position:

• chr6-117675698-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138459.5(NUS1):​c.28C>G​(p.Arg10Gly) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NUS1 NM_138459.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUS1	NM_138459.5	c.28C>G	p.Arg10Gly	missense_variant	1/5	ENST00000368494.4	NP_612468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUS1	ENST00000368494.4	c.28C>G	p.Arg10Gly	missense_variant	1/5	1	NM_138459.5	ENSP00000357480	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.28C>G (p.R10G) alteration is located in exon 1 (coding exon 1) of the NUS1 gene. This alteration results from a C to G substitution at nucleotide position 28, causing the arginine (R) at amino acid position 10 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.63		Loss of MoRF binding (P = 0.0188);
MVP		0.41
MPC		3.5
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.80

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: chr6-117996861;