rs778592524

Variant names:

• chr6-117675692-G-A
• rs778592524
• NM_138459.5:c.22G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-117675692-G-A
• chr6-117675692-G-C
• chr6-117675692-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138459.5(NUS1):​c.22G>A​(p.Val8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,495,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NUS1 NM_138459.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000289372 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33837986).

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.22G>A	p.Val8Met	missense	Exon 1 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.22G>A	p.Val8Met	missense	Exon 1 of 5	ENSP00000357480.3	Q96E22
	NUS1	ENST00000885063.1		c.22G>A	p.Val8Met	missense	Exon 1 of 6	ENSP00000555122.1
	NUS1	ENST00000923852.1		c.22G>A	p.Val8Met	missense	Exon 1 of 3	ENSP00000593911.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151540 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.44e-7 AC: 1 AN: 1344022 Hom.: 0 Cov.: 26 AF XY: 0.00000151 AC XY: 1 AN XY: 663594

African (AFR) AF: 0.00 AC: 0 AN: 31796

American (AMR) AF: 0.00 AC: 0 AN: 36540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23324

East Asian (EAS) AF: 0.00 AC: 0 AN: 37054

South Asian (SAS) AF: 0.00 AC: 0 AN: 74718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3930

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043732

Other (OTH) AF: 0.00 AC: 0 AN: 56366

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151540 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73966

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67714

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.12
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.038	D
Polyphen		0.87	P
Vest4		0.49
MutPred		0.54		Gain of disorder (P = 0.0621)
MVP		0.12
MPC		2.1
ClinPred		0.66	D
GERP RS		5.1
PromoterAI		0.039	Neutral
Varity_R		0.17
gMVP		0.26
Mutation Taster		=82/18	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: rs778592524; hg19: chr6-117996855;