chr16-56748435-T-G

Variant names:

• chr16-56748435-T-G
• rs189526861
• NM_014669.5:c.179+9T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_014669.5(NUP93):​c.179+9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,606,122 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: NUP93 NM_014669.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.553
• Publications: 0 publications found

Genes affected

NUP93 (HGNC:28958): (nucleoporin 93) The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. This gene encodes a nucleoporin protein that localizes both to the basket of the pore and to the nuclear entry of the central gated channel of the pore. The encoded protein is a target of caspase cysteine proteases that play a central role in programmed cell death by apoptosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

NUP93 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  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=-0.24).
• BP6: Variant 16-56748435-T-G is Benign according to our data. Variant chr16-56748435-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1635121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00363 (553/152304) while in subpopulation AFR AF = 0.00835 (347/41576). AF 95% confidence interval is 0.00762. There are 1 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014669.5. 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
	NUP93	NM_014669.5	MANE Select	c.179+9T>G		intron	N/A	NP_055484.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	ENST00000308159.10	TSL:1 MANE Select	c.179+9T>G		intron	N/A	ENSP00000310668.5	Q8N1F7-1
	NUP93	ENST00000569842.5	TSL:5	c.179+9T>G		intron	N/A	ENSP00000458101.1	H3BVG0
	NUP93	ENST00000923937.1		c.179+9T>G		intron	N/A	ENSP00000593996.1

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00839

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00213 AC: 525 AN: 246234 AF XY: 0.00184

Gnomad AFR exome AF: 0.00903

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00779

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00111 AC: 1618 AN: 1453818 Hom.: 5 Cov.: 30 AF XY: 0.00107 AC XY: 776 AN XY: 721876

African (AFR) AF: 0.00835 AC: 278 AN: 33298

American (AMR) AF: 0.00367 AC: 163 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00873 AC: 227 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00632 AC: 35 AN: 5542

European-Non Finnish (NFE) AF: 0.000671 AC: 742 AN: 1106412

Other (OTH) AF: 0.00287 AC: 172 AN: 60034

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74488

African (AFR) AF: 0.00835 AC: 347 AN: 41576

American (AMR) AF: 0.00471 AC: 72 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00252 Hom.: 2

Bravo AF: 0.00448

Asia WGS AF: 0.00144 AC: 6 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	Nephrotic syndrome, type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		0.55
PromoterAI		0.044	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs189526861; hg19: chr16-56782347;