chr19-49909248-G-A

Position:

• chr19-49909248-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016553.5(NUP62):​c.560C>T​(p.Thr187Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000882 in 1,614,102 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T187T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: NUP62 NM_016553.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.465

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 (MetaRNN=0.0042422414).
• BP6: Variant 19-49909248-G-A is Benign according to our data. Variant chr19-49909248-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49909248-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00469 (714/152260) while in subpopulation AFR AF= 0.0161 (667/41542). AF 95% confidence interval is 0.015. There are 2 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP62	NM_016553.5	c.560C>T	p.Thr187Met	missense_variant	3/3	ENST00000352066.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP62	ENST00000352066.8	c.560C>T	p.Thr187Met	missense_variant	3/3	1	NM_016553.5	P1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00121 AC: 303 AN: 251234 Hom.: 3 AF XY: 0.000817 AC XY: 111 AN XY: 135816

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000486 AC: 710 AN: 1461842 Hom.: 5 Cov.: 36 AF XY: 0.000413 AC XY: 300 AN XY: 727218

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74440

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000782 Hom.: 0

Bravo AF: 0.00550

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.061	T;T;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	.;.;.;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N;.;.;.
REVEL	Benign	0.028
Sift	Uncertain	0.019	D;D;.;.;.
Sift4G	Uncertain	0.046	D;D;D;T;D
Polyphen		0.30	B;B;B;.;B
Vest4		0.097
MVP		0.24
MPC		0.22
ClinPred		0.0046	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.40

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: rs140655913; hg19: chr19-50412505;