1-179551016-C-T

Variant names:

• chr1-179551016-C-T
• rs1410590
• NM_014625.4:c.*157G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*157G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3496C>T		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.*157G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3496C>T		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

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

African (AFR) AF: 0.851 AC: 14808 AN: 17400

American (AMR) AF: 0.954 AC: 28642 AN: 30012

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 16426 AN: 18084

East Asian (EAS) AF: 0.971 AC: 31560 AN: 32498

South Asian (SAS) AF: 0.885 AC: 51698 AN: 58440

European-Finnish (FIN) AF: 0.944 AC: 33036 AN: 35014

Middle Eastern (MID) AF: 0.883 AC: 2411 AN: 2732

European-Non Finnish (NFE) AF: 0.932 AC: 418266 AN: 448826

Other (OTH) AF: 0.923 AC: 31444 AN: 34082

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

African (AFR) AF: 0.851 AC: 35350 AN: 41518

American (AMR) AF: 0.937 AC: 14326 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3134 AN: 3468

East Asian (EAS) AF: 0.964 AC: 5000 AN: 5186

South Asian (SAS) AF: 0.878 AC: 4234 AN: 4822

European-Finnish (FIN) AF: 0.931 AC: 9885 AN: 10616

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63252 AN: 68032

Other (OTH) AF: 0.894 AC: 1888 AN: 2112

Alfa AF: 0.922 Hom.: 105777

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.46
DANN	Benign	0.69
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1410590; hg19: chr1-179520151;