1-179550745-T-C

Variant names:

• chr1-179550745-T-C
• rs1060775
• NM_014625.4:c.*428A>G

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.*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
• Publications: 2 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=-0.89).
• 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 rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*428A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3767T>C		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.*428A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3767T>C		intron_variant	Intron 25 of 25	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

African (AFR) AF: 0.839 AC: 2103 AN: 2508

American (AMR) AF: 0.949 AC: 3953 AN: 4166

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 1513 AN: 1650

East Asian (EAS) AF: 0.964 AC: 4130 AN: 4284

South Asian (SAS) AF: 0.884 AC: 6643 AN: 7512

European-Finnish (FIN) AF: 0.946 AC: 2453 AN: 2594

Middle Eastern (MID) AF: 0.848 AC: 229 AN: 270

European-Non Finnish (NFE) AF: 0.937 AC: 38539 AN: 41130

Other (OTH) AF: 0.923 AC: 3487 AN: 3776

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

African (AFR) AF: 0.842 AC: 34913 AN: 41478

American (AMR) AF: 0.936 AC: 14307 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3136 AN: 3470

East Asian (EAS) AF: 0.964 AC: 4980 AN: 5164

South Asian (SAS) AF: 0.878 AC: 4223 AN: 4810

European-Finnish (FIN) AF: 0.931 AC: 9873 AN: 10602

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

European-Non Finnish (NFE) AF: 0.930 AC: 63236 AN: 68018

Other (OTH) AF: 0.892 AC: 1883 AN: 2110

Alfa AF: 0.920 Hom.: 54308

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

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

not provided Benign:1

-

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	-0.89
CADD	Benign	1.3
DANN	Benign	0.41
PhyloP100		0.26
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: rs1060775; hg19: chr1-179519880;