chr9-128947846-A-G

Variant names:

• chr9-128947846-A-G
• rs113527732
• NM_015354.3:c.32+95A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015354.3(NUP188):​c.32+95A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,219,244 control chromosomes in the GnomAD database, including 892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (487 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (405 hom.)
• Consequence: NUP188 NM_015354.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-128947846-A-G is Benign according to our data. Variant chr9-128947846-A-G is described in ClinVar as [Benign]. Clinvar id is 676304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP188	NM_015354.3	c.32+95A>G		intron_variant	Intron 1 of 43	ENST00000372577.2	NP_056169.1
DOLK	NM_014908.4	c.-543T>C		upstream_gene_variant		ENST00000372586.4	NP_055723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP188	ENST00000372577.2	c.32+95A>G		intron_variant	Intron 1 of 43	1	NM_015354.3	ENSP00000361658.2
ENSG00000251184	ENST00000482796.1	c.39-1343A>G		intron_variant	Intron 1 of 4	2		ENSP00000417556.2
DOLK	ENST00000372586.4	c.-543T>C		upstream_gene_variant		6	NM_014908.4	ENSP00000361667.3

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6869 AN: 151644 Hom.: 479 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000840

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.00739 AC: 7892 AN: 1067484 Hom.: 405 Cov.: 16 AF XY: 0.00736 AC XY: 3781 AN XY: 514052

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0686

Gnomad4 SAS exome AF: 0.0256

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0455 AC: 6901 AN: 151760 Hom.: 487 Cov.: 31 AF XY: 0.0444 AC XY: 3288 AN XY: 74116

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0392

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000825

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.00709 Hom.: 8

Bravo AF: 0.0512

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.94
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs113527732; hg19: chr9-131710125;