6-117675676-G-C

Variant names:

• chr6-117675676-G-C
• rs753550769
• NM_138459.5:c.6G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_138459.5(NUS1):​c.6G>C​(p.Thr2Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,467,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: NUS1 NM_138459.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-117675676-G-C is Benign according to our data. Variant chr6-117675676-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2158836.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.

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.6G>C	p.Thr2Thr	synonymous	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.6G>C	p.Thr2Thr	synonymous	Exon 1 of 5	ENSP00000357480.3	Q96E22
	NUS1	ENST00000885063.1		c.6G>C	p.Thr2Thr	synonymous	Exon 1 of 6	ENSP00000555122.1
	NUS1	ENST00000923852.1		c.6G>C	p.Thr2Thr	synonymous	Exon 1 of 3	ENSP00000593911.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151536 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000283 AC: 4 AN: 141330 AF XY: 0.0000262

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: 0.000141

Gnomad NFE exome AF: 0.0000561

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 32 AN: 1315718 Hom.: 0 Cov.: 20 AF XY: 0.0000198 AC XY: 13 AN XY: 655152

African (AFR) AF: 0.00 AC: 0 AN: 31342

American (AMR) AF: 0.00 AC: 0 AN: 38628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24654

East Asian (EAS) AF: 0.00 AC: 0 AN: 37404

South Asian (SAS) AF: 0.00 AC: 0 AN: 79002

European-Finnish (FIN) AF: 0.0000255 AC: 1 AN: 39160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3916

European-Non Finnish (NFE) AF: 0.0000308 AC: 31 AN: 1006146

Other (OTH) AF: 0.00 AC: 0 AN: 55466

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151536 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73962

African (AFR) AF: 0.00 AC: 0 AN: 41306

American (AMR) AF: 0.00 AC: 0 AN: 15238

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67746

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital disorder of glycosylation, type IAA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		2.0
PromoterAI		-0.028	Neutral

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: rs753550769; hg19: chr6-117996839;