1-179551016-C-T

Position:

• chr1-179551016-C-T

Variant summary

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

The NM_014625.4(NPHS2):​c.*157G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 829,342 control chromosomes in the GnomAD database, including 354,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62802 hom., cov: 32)
  • Exomes 𝑓: 0.93 (291840 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.54

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-179551016-C-T is Benign according to our data. Variant chr1-179551016-C-T is described in ClinVar as [Benign]. Clinvar id is 224483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.*157G>A		3_prime_UTR_variant	8/8	ENST00000367615.9
AXDND1	NM_144696.6	c.3032-3496C>T		intron_variant		ENST00000367618.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.*157G>A		3_prime_UTR_variant	8/8	1	NM_014625.4	P1
AXDND1	ENST00000367618.8	c.3032-3496C>T		intron_variant		1	NM_144696.6	P2

Frequencies

GnomAD3 genomes AF: 0.907 AC: 138022 AN: 152136 Hom.: 62758 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.875

Gnomad AMR AF: 0.937

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.893

GnomAD4 exome AF: 0.928 AC: 628291 AN: 677088 Hom.: 291840 Cov.: 9 AF XY: 0.926 AC XY: 327031 AN XY: 353268

Gnomad4 AFR exome AF: 0.851

Gnomad4 AMR exome AF: 0.954

Gnomad4 ASJ exome AF: 0.908

Gnomad4 EAS exome AF: 0.971

Gnomad4 SAS exome AF: 0.885

Gnomad4 FIN exome AF: 0.944

Gnomad4 NFE exome AF: 0.932

Gnomad4 OTH exome AF: 0.923

GnomAD4 genome AF: 0.907 AC: 138126 AN: 152254 Hom.: 62802 Cov.: 32 AF XY: 0.908 AC XY: 67546 AN XY: 74430

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.937

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.964

Gnomad4 SAS AF: 0.878

Gnomad4 FIN AF: 0.931

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.894

Alfa AF: 0.923 Hom.: 83339

Bravo AF: 0.907

Asia WGS AF: 0.916 AC: 3185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Human Genetics Disease in Children – Taif University, Taif University	Jan 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.46
DANN	Benign	0.69

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: rs1410590; hg19: chr1-179520151;