rs9767451

Variant names:

• chr6-117675655-T-C
• rs9767451
• NM_138459.5:c.-16T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-117675655-T-C
• chr6-117675655-T-A
• chr6-117675655-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138459.5(NUS1):​c.-16T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 148,260 control chromosomes in the GnomAD database, including 67,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.95 (67057 hom., cov: 22)
  • Exomes 𝑓: 0.99 (587666 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUS1 NM_138459.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.860
• Publications: 10 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), Ambry Genetics, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-117675655-T-C is Benign according to our data. Variant chr6-117675655-T-C is described in ClinVar as Benign. ClinVar VariationId is 1327053.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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.-16T>C		5_prime_UTR	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.-16T>C		5_prime_UTR	Exon 1 of 5	ENSP00000357480.3	Q96E22
	NUS1	ENST00000885063.1		c.-16T>C		5_prime_UTR	Exon 1 of 6	ENSP00000555122.1
	NUS1	ENST00000923852.1		c.-16T>C		5_prime_UTR	Exon 1 of 3	ENSP00000593911.1

Frequencies

GnomAD3 genomes AF: 0.949 AC: 140599 AN: 148162 Hom.: 67016 Cov.: 22

Gnomad AFR AF: 0.857

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.990

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.956

GnomAD2 exomes AF: 0.948 AC: 112478 AN: 118648 AF XY: 0.957

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.914

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.972

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.978

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.987 AC: 1188454 AN: 1204086 Hom.: 587666 Cov.: 17 AF XY: 0.988 AC XY: 595258 AN XY: 602536

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

African (AFR) AF: 0.854 AC: 22913 AN: 26828

American (AMR) AF: 0.926 AC: 32957 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 23304 AN: 23348

East Asian (EAS) AF: 0.841 AC: 29180 AN: 34710

South Asian (SAS) AF: 0.994 AC: 75115 AN: 75574

European-Finnish (FIN) AF: 0.981 AC: 36756 AN: 37462

Middle Eastern (MID) AF: 0.993 AC: 3644 AN: 3670

European-Non Finnish (NFE) AF: 0.999 AC: 914265 AN: 915432

Other (OTH) AF: 0.978 AC: 50320 AN: 51454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.949 AC: 140689 AN: 148260 Hom.: 67057 Cov.: 22 AF XY: 0.948 AC XY: 68457 AN XY: 72192

African (AFR) AF: 0.857 AC: 34239 AN: 39940

American (AMR) AF: 0.957 AC: 14397 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3460 AN: 3462

East Asian (EAS) AF: 0.842 AC: 4122 AN: 4898

South Asian (SAS) AF: 0.990 AC: 4570 AN: 4616

European-Finnish (FIN) AF: 0.982 AC: 9837 AN: 10020

Middle Eastern (MID) AF: 0.990 AC: 287 AN: 290

European-Non Finnish (NFE) AF: 0.998 AC: 66917 AN: 67040

Other (OTH) AF: 0.954 AC: 1970 AN: 2064

Alfa AF: 0.975 Hom.: 13074

Bravo AF: 0.941

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.0
DANN	Benign	0.50
PhyloP100		-0.86
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	polymorphism (auto)

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: rs9767451; hg19: chr6-117996818; COSMIC: COSV63844470;