9-128947707-C-T

Variant names:

• chr9-128947707-C-T
• rs3750324
• NM_015354.3:c.-13C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015354.3(NUP188):​c.-13C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,465,358 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (137 hom.)
• Consequence: NUP188 NM_015354.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.35

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-128947707-C-T is Benign according to our data. Variant chr9-128947707-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 365207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP188	NM_015354.3	c.-13C>T		5_prime_UTR_variant	Exon 1 of 44	ENST00000372577.2	NP_056169.1
DOLK	NM_014908.4	c.-404G>A		upstream_gene_variant		ENST00000372586.4	NP_055723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP188	ENST00000372577	c.-13C>T		5_prime_UTR_variant	Exon 1 of 44	1	NM_015354.3	ENSP00000361658.2
ENSG00000251184	ENST00000482796.1	c.39-1482C>T		intron_variant	Intron 1 of 4	2		ENSP00000417556.2
NUP188	ENST00000491990.5	n.1C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5
DOLK	ENST00000372586.4	c.-404G>A		upstream_gene_variant		6	NM_014908.4	ENSP00000361667.3

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152058 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0394

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00744 AC: 636 AN: 85520 Hom.: 17 AF XY: 0.00894 AC XY: 417 AN XY: 46620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0294

Gnomad SAS exome AF: 0.0287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000604

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00323 AC: 4241 AN: 1313182 Hom.: 137 Cov.: 31 AF XY: 0.00387 AC XY: 2489 AN XY: 643042

Gnomad4 AFR exome AF: 0.000107

Gnomad4 AMR exome AF: 0.0000397

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0644

Gnomad4 SAS exome AF: 0.0267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000623

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152176 Hom.: 7 Cov.: 31 AF XY: 0.00288 AC XY: 214 AN XY: 74398

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0385

Gnomad4 SAS AF: 0.0300

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely 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. -

DK1-congenital disorder of glycosylation Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3750324; hg19: chr9-131709986;