1-179550745-T-C

Position:

• chr1-179550745-T-C

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.*428A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 220,034 control chromosomes in the GnomAD database, including 91,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62401 hom., cov: 30)
  • Exomes 𝑓: 0.93 (29333 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.264

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)

AXDND1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-179550745-T-C is Benign according to our data. Variant chr1-179550745-T-C is described in ClinVar as [Benign]. Clinvar id is 224486.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	Protein	UniProt
NPHS2	NM_014625.4	c.*428A>G		3_prime_UTR_variant	8/8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3767T>C		intron_variant		ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615	c.*428A>G		3_prime_UTR_variant	8/8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3767T>C		intron_variant		1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137506 AN: 152026 Hom.: 62357 Cov.: 30

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.875

Gnomad AMR AF: 0.936

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: 0.891

GnomAD4 exome AF: 0.929 AC: 63050 AN: 67890 Hom.: 29333 Cov.: 0 AF XY: 0.925 AC XY: 32032 AN XY: 34612

Gnomad4 AFR exome AF: 0.839

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.917

Gnomad4 EAS exome AF: 0.964

Gnomad4 SAS exome AF: 0.884

Gnomad4 FIN exome AF: 0.946

Gnomad4 NFE exome AF: 0.937

Gnomad4 OTH exome AF: 0.923

GnomAD4 genome AF: 0.904 AC: 137608 AN: 152144 Hom.: 62401 Cov.: 30 AF XY: 0.905 AC XY: 67303 AN XY: 74374

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.936

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: 0.892

Alfa AF: 0.924 Hom.: 38160

Bravo AF: 0.904

Asia WGS AF: 0.915 AC: 3182 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Human Genetics Disease in Children – Taif University, Taif University	Jan 01, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.41

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: rs1060775; hg19: chr1-179519880;