9-128947707-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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), PanelApp Australia, ClinGen, Orphanet, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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.-13C>T		5_prime_UTR	Exon 1 of 44	NP_056169.1	Q5SRE5-1
	DOLK	NM_014908.4	MANE Select	c.-404G>A		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.-13C>T		5_prime_UTR	Exon 1 of 44	ENSP00000361658.2	Q5SRE5-1
	ENSG00000251184	ENST00000482796.1	TSL:2	c.39-1482C>T		intron	N/A	ENSP00000417556.2	H7C4K7
	NUP188	ENST00000935260.1		c.-13C>T		5_prime_UTR	Exon 1 of 45	ENSP00000605319.1

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

GnomAD2 exomes AF: 0.00744 AC: 636 AN: 85520 AF XY: 0.00894

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 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

African (AFR) AF: 0.000107 AC: 3 AN: 27964

American (AMR) AF: 0.0000397 AC: 1 AN: 25212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21366

East Asian (EAS) AF: 0.0644 AC: 2115 AN: 32862

South Asian (SAS) AF: 0.0267 AC: 1860 AN: 69792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33668

Middle Eastern (MID) AF: 0.00109 AC: 5 AN: 4604

European-Non Finnish (NFE) AF: 0.0000623 AC: 65 AN: 1043246

Other (OTH) AF: 0.00353 AC: 192 AN: 54468

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0385 AC: 197 AN: 5112

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67992

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DK1-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		1.3
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=296/4	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: rs3750324; hg19: chr9-131709986;