12-102101071-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_024057.4(NUP37):c.315A>G(p.Arg105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,561,180 control chromosomes in the GnomAD database, including 644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (79 hom., cov: 32)
  • Exomes 𝑓: 0.025 (565 hom.)
• Consequence: NUP37 NM_024057.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

Genes affected

NUP37 (HGNC:29929): (nucleoporin 37) Nuclear pore complexes (NPCs) are used for transporting macromolecules between the cytoplasm and the nucleus. NPCs consist of multiple copies of 30 distinct proteins (nucleoporins), which assemble into biochemically-separable subcomplexes. The protein encoded by this gene is part of a subcomplex (Nup107-160) that is required for proper NPC function as well as for normal kinetochore-microtubule interaction and mitosis. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-102101071-T-C is Benign according to our data. Variant chr12-102101071-T-C is described in ClinVar as [Benign]. Clinvar id is 3037376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.089 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0282 (4299/152268) while in subpopulation AFR AF= 0.0331 (1375/41554). AF 95% confidence interval is 0.0316. There are 79 homozygotes in gnomad4. There are 2087 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP37	NM_024057.4	c.315A>G	p.Arg105=	synonymous_variant	4/10	ENST00000552283.6
NUP37	XM_047429530.1	c.315A>G	p.Arg105=	synonymous_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP37	ENST00000552283.6	c.315A>G	p.Arg105=	synonymous_variant	4/10	5	NM_024057.4	P1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4294 AN: 152150 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0245 AC: 5496 AN: 224202 Hom.: 115 AF XY: 0.0248 AC XY: 3019 AN XY: 121930

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0254 AC: 35790 AN: 1408912 Hom.: 565 Cov.: 25 AF XY: 0.0254 AC XY: 17821 AN XY: 700332

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.00949

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.0458

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0223

GnomAD4 genome AF: 0.0282 AC: 4299 AN: 152268 Hom.: 79 Cov.: 32 AF XY: 0.0280 AC XY: 2087 AN XY: 74450

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0296 Hom.: 35

Bravo AF: 0.0259

Asia WGS AF: 0.00982 AC: 35 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NUP37-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.8
Dann	Benign	0.67

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: rs17438178; hg19: chr12-102494849;