rs192920839

Variant names:

• chr6-117675486-G-A
• rs192920839
• NM_138459.5:c.-185G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_138459.5(NUS1):​c.-185G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00268 in 614,824 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (5 hom.)
• Consequence: NUS1 NM_138459.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.06
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 6-117675486-G-A is Benign according to our data. Variant chr6-117675486-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1706275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00818 (1230/150356) while in subpopulation AFR AF = 0.028 (1158/41392). AF 95% confidence interval is 0.0266. There are 14 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

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.-185G>A		5_prime_UTR	Exon 1 of 5	NP_612468.1	Q96E22
	LOC101927919	NR_110854.1		n.-202C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUS1	ENST00000368494.4	TSL:1 MANE Select	c.-185G>A		5_prime_UTR	Exon 1 of 5	ENSP00000357480.3	Q96E22
	ENSG00000289372	ENST00000815931.1		n.35+253C>T		intron	N/A
	NUS1	ENST00000885063.1		c.-185G>A		upstream_gene	N/A	ENSP00000555122.1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1220 AN: 150236 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00336

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00673

GnomAD4 exome AF: 0.000902 AC: 419 AN: 464468 Hom.: 5 Cov.: 5 AF XY: 0.000721 AC XY: 178 AN XY: 246934

African (AFR) AF: 0.0269 AC: 309 AN: 11494

American (AMR) AF: 0.00207 AC: 40 AN: 19352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13630

East Asian (EAS) AF: 0.0000658 AC: 2 AN: 30406

South Asian (SAS) AF: 0.00 AC: 0 AN: 47494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29558

Middle Eastern (MID) AF: 0.00150 AC: 3 AN: 2004

European-Non Finnish (NFE) AF: 0.0000739 AC: 21 AN: 284050

Other (OTH) AF: 0.00166 AC: 44 AN: 26480

GnomAD4 genome AF: 0.00818 AC: 1230 AN: 150356 Hom.: 14 Cov.: 31 AF XY: 0.00792 AC XY: 583 AN XY: 73610

African (AFR) AF: 0.0280 AC: 1158 AN: 41392

American (AMR) AF: 0.00336 AC: 51 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000752 AC: 5 AN: 66502

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.00596 Hom.: 0

Bravo AF: 0.00923

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
PhyloP100		5.1
PromoterAI		0.11	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs192920839; hg19: chr6-117996649;