6-117675655-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138459.5(NUS1):​c.-16T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUS1 NM_138459.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 148256 Hom.: 0 Cov.: 22

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000506 AC: 6 AN: 118648 AF XY: 0.0000772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000414 AC: 5 AN: 1207474 Hom.: 0 Cov.: 17 AF XY: 0.00000497 AC XY: 3 AN XY: 604062

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

African (AFR) AF: 0.0000354 AC: 1 AN: 28254

American (AMR) AF: 0.00 AC: 0 AN: 35994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23362

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35286

South Asian (SAS) AF: 0.00 AC: 0 AN: 75638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3678

European-Non Finnish (NFE) AF: 0.00000218 AC: 2 AN: 915942

Other (OTH) AF: 0.0000193 AC: 1 AN: 51776

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 148256 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 72126

African (AFR) AF: 0.00 AC: 0 AN: 39886

American (AMR) AF: 0.00 AC: 0 AN: 15038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.00 AC: 0 AN: 4624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10026

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67050

Other (OTH) AF: 0.00 AC: 0 AN: 2042

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		-0.86
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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;