19-49908485-A-G

Variant summary

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

The NM_016553.5(NUP62):c.1323T>C(p.Asp441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,614,114 control chromosomes in the GnomAD database, including 701,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69048 hom., cov: 33)
  • Exomes 𝑓: 0.93 (632494 hom.)
• Consequence: NUP62 NM_016553.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0350

Genes affected

NUP62 (HGNC:8066): (nucleoporin 62) 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. The protein encoded by this gene is a member of the FG-repeat containing nucleoporins and is localized to the nuclear pore central plug. This protein associates with the importin alpha/beta complex which is involved in the import of proteins containing nuclear localization signals. Multiple transcript variants of this gene encode a single protein isoform. [provided by RefSeq, Jul 2008]

IL4I1 (HGNC:19094): (interleukin 4 induced 1) This gene encodes a secreted L-amino acid oxidase protein which primarily catabolizes L-phenylalanine and, to a lesser extent, L-arginine. The expression of this gene is induced by the cytokine interleukin 4 in B cells. This gene is also expressed in macrophages and dendritic cells. This protein may play a role immune system escape as it is expressed in tumor-associated macrophages and suppresses T-cell responses. This protein also contains domains thought to be involved in the binding of flavin adenine dinucleotide (FAD) cofactor. Multiple transcript variants encoding different isoforms have been found for this gene. Some transcripts of this gene share a promoter and exons of the 5' UTR with the overlapping NUP62 gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-49908485-A-G is Benign according to our data. Variant chr19-49908485-A-G is described in ClinVar as [Benign]. Clinvar id is 129846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49908485-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP62	NM_016553.5	c.1323T>C	p.Asp441=	synonymous_variant	3/3	ENST00000352066.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP62	ENST00000352066.8	c.1323T>C	p.Asp441=	synonymous_variant	3/3	1	NM_016553.5	P1

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144864 AN: 152202 Hom.: 68987 Cov.: 33

Gnomad AFR AF: 0.987

Gnomad AMI AF: 0.935

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.941

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.943

GnomAD3 exomes AF: 0.944 AC: 236360 AN: 250348 Hom.: 111671 AF XY: 0.942 AC XY: 127432 AN XY: 135282

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.967

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.946

Gnomad FIN exome AF: 0.940

Gnomad NFE exome AF: 0.926

Gnomad OTH exome AF: 0.932

GnomAD4 exome AF: 0.930 AC: 1359454 AN: 1461794 Hom.: 632494 Cov.: 100 AF XY: 0.930 AC XY: 676292 AN XY: 727194

Gnomad4 AFR exome AF: 0.989

Gnomad4 AMR exome AF: 0.967

Gnomad4 ASJ exome AF: 0.899

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.945

Gnomad4 FIN exome AF: 0.940

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.935

GnomAD4 genome AF: 0.952 AC: 144984 AN: 152320 Hom.: 69048 Cov.: 33 AF XY: 0.953 AC XY: 70955 AN XY: 74478

Gnomad4 AFR AF: 0.987

Gnomad4 AMR AF: 0.957

Gnomad4 ASJ AF: 0.905

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.945

Gnomad4 FIN AF: 0.941

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.944

Alfa AF: 0.934 Hom.: 36682

Bravo AF: 0.954

Asia WGS AF: 0.973 AC: 3383 AN: 3478

EpiCase AF: 0.929

EpiControl AF: 0.927

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Infantile bilateral striatal necrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.087
Dann	Benign	0.58

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: rs892028; hg19: chr19-50411742;