chr12-68735334-A-C

Position:

• chr12-68735334-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_020401.4(NUP107):​c.2492A>C​(p.Asp831Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NUP107 NM_020401.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.26

Genes affected

NUP107 (HGNC:29914): (nucleoporin 107) This gene encodes a member of the nucleoporin family. The protein is localized to the nuclear rim and is an essential component of the nuclear pore complex (NPC). All molecules entering or leaving the nucleus either diffuse through or are actively transported by the NPC. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 12-68735334-A-C is Pathogenic according to our data. Variant chr12-68735334-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 219127.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP107	NM_020401.4	c.2492A>C	p.Asp831Ala	missense_variant	26/28	ENST00000229179.9	NP_065134.1
NUP107	NM_001330192.2	c.2405A>C	p.Asp802Ala	missense_variant	26/28		NP_001317121.1
NUP107	XM_005269037.5	c.2432A>C	p.Asp811Ala	missense_variant	25/27		XP_005269094.1
NUP107	XM_047429177.1	c.1556A>C	p.Asp519Ala	missense_variant	16/18		XP_047285133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP107	ENST00000229179.9	c.2492A>C	p.Asp831Ala	missense_variant	26/28	1	NM_020401.4	ENSP00000229179	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251334 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460560 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 11 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NUP107 related disorder (ClinVar ID: VCV000219127, PMID:26411495, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 26411495, PM3_S) and it was co-segregated with Nephrotic syndrome, type 11 in multiple affected family members (PMID: 26411495, PP1_P). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (, PS3_S). A missense variant is a common mechanism associated with Nephrotic syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.86		Loss of solvent accessibility (P = 0.0509);.;.;
MVP		0.75
MPC		1.0
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.88
gMVP		0.77

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: rs864321632; hg19: chr12-69129114;