chr1-179550915-T-C

Position:

• chr1-179550915-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.*258A>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 0.273 in 512,930 control chromosomes in the GnomAD database, including 20,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4898 hom., cov: 32)
  • Exomes 𝑓: 0.29 (15691 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.259

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=-0.82).
• BP6: Variant 1-179550915-T-C is Benign according to our data. Variant chr1-179550915-T-C is described in ClinVar as [Benign]. Clinvar id is 224485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.*258A>G		3_prime_UTR_variant	8/8	ENST00000367615.9
AXDND1	NM_144696.6	c.3032-3597T>C		intron_variant		ENST00000367618.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.*258A>G		3_prime_UTR_variant	8/8	1	NM_014625.4	P1
AXDND1	ENST00000367618.8	c.3032-3597T>C		intron_variant		1	NM_144696.6	P2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36751 AN: 151984 Hom.: 4892 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.286 AC: 103298 AN: 360826 Hom.: 15691 Cov.: 4 AF XY: 0.290 AC XY: 55549 AN XY: 191260

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.242 AC: 36768 AN: 152104 Hom.: 4898 Cov.: 32 AF XY: 0.243 AC XY: 18041 AN XY: 74352

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.271

Alfa AF: 0.283 Hom.: 12928

Bravo AF: 0.241

Asia WGS AF: 0.374 AC: 1301 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
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, 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

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.73

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: rs2274622; hg19: chr1-179520050;