rs746695959

Variant names:

• chr9-128947727-C-A
• rs746695959
• NM_015354.3:c.8C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-128947727-C-A
• chr9-128947727-C-G
• chr9-128947727-C-T

Variant summary

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

The NM_015354.3(NUP188):​c.8C>A​(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,315,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: NUP188 NM_015354.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 1 publications found

Genes affected

NUP188 (HGNC:17859): (nucleoporin 188) The nuclear pore complex (NPC) is found on the nuclear envelope and forms a gateway that regulates the flow of proteins and RNAs between the cytoplasm and nucleoplasm. The NPC is comprised of approximately 30 distinct proteins collectively known as nucleoporins. Nucleoporins are pore-complex-specific glycoproteins which often have cytoplasmically oriented O-linked N-acetylglucosamine residues and numerous repeats of the pentapeptide sequence XFXFG. However, the nucleoporin protein encoded by this gene does not contain the typical FG repeat sequences found in most vertebrate nucleoporins. This nucleoporin is thought to form part of the scaffold for the central channel of the nuclear pore. [provided by RefSeq, Jan 2013]

ENSG00000251184 (HGNC:):

DOLK (HGNC:23406): (dolichol kinase) The protein encoded by this gene catalyzes the CTP-mediated phosphorylation of dolichol, and is involved in the synthesis of Dol-P-Man, which is an essential glycosyl carrier lipid for C- and O-mannosylation, N- and O-linked glycosylation of proteins, and for the biosynthesis of glycosyl phosphatidylinositol anchors in endoplasmic reticulum. Mutations in this gene are associated with dolichol kinase deficiency.[provided by RefSeq, Apr 2010]

DOLK Gene-Disease associations (from GenCC):

• DK1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.28580385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015354.3. 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
	NUP188	NM_015354.3	MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 1 of 44	NP_056169.1	Q5SRE5-1
	DOLK	NM_014908.4	MANE Select	c.-424G>T		upstream_gene	N/A	NP_055723.1	Q9UPQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP188	ENST00000372577.2	TSL:1 MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 1 of 44	ENSP00000361658.2	Q5SRE5-1
	ENSG00000251184	ENST00000482796.1	TSL:2	c.39-1462C>A		intron	N/A	ENSP00000417556.2	H7C4K7
	NUP188	ENST00000935260.1		c.8C>A	p.Ala3Glu	missense	Exon 1 of 45	ENSP00000605319.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1315996 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 645094

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

African (AFR) AF: 0.00 AC: 0 AN: 27716

American (AMR) AF: 0.00 AC: 0 AN: 25498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21700

East Asian (EAS) AF: 0.00 AC: 0 AN: 32624

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4890

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044272

Other (OTH) AF: 0.00 AC: 0 AN: 54518

⚠️ 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 Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.0031
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.098	T
Polyphen		0.94	P
Vest4		0.49
MutPred		0.30		Gain of solvent accessibility (P = 0.005)
MVP		0.18
MPC		0.21
ClinPred		0.69	D
GERP RS		3.7
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.37
gMVP		0.58
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746695959; hg19: chr9-131710006;