1-179550973-C-T

Variant names:

• chr1-179550973-C-T
• rs2274623
• NM_014625.4:c.*200G>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.*200G>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 0.2 in 652,868 control chromosomes in the GnomAD database, including 14,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2489 hom., cov: 32)
  • Exomes 𝑓: 0.21 (11990 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.117
• Publications: 8 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=-0.83).
• BP6: Variant 1-179550973-C-T is Benign according to our data. Variant chr1-179550973-C-T is described in ClinVar as [Benign]. Clinvar id is 224484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*200G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3539C>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.*200G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3539C>T		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24595 AN: 152054 Hom.: 2494 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.211 AC: 105822 AN: 500696 Hom.: 11990 Cov.: 6 AF XY: 0.214 AC XY: 56587 AN XY: 264270

African (AFR) AF: 0.0398 AC: 546 AN: 13702

American (AMR) AF: 0.226 AC: 5238 AN: 23190

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 2470 AN: 14704

East Asian (EAS) AF: 0.354 AC: 10850 AN: 30692

South Asian (SAS) AF: 0.257 AC: 12503 AN: 48700

European-Finnish (FIN) AF: 0.187 AC: 5425 AN: 28946

Middle Eastern (MID) AF: 0.170 AC: 355 AN: 2092

European-Non Finnish (NFE) AF: 0.203 AC: 63133 AN: 311018

Other (OTH) AF: 0.192 AC: 5302 AN: 27652

GnomAD4 genome AF: 0.162 AC: 24586 AN: 152172 Hom.: 2489 Cov.: 32 AF XY: 0.165 AC XY: 12278 AN XY: 74370

African (AFR) AF: 0.0411 AC: 1707 AN: 41546

American (AMR) AF: 0.202 AC: 3086 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3468

East Asian (EAS) AF: 0.346 AC: 1795 AN: 5182

South Asian (SAS) AF: 0.265 AC: 1274 AN: 4816

European-Finnish (FIN) AF: 0.177 AC: 1870 AN: 10566

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13780 AN: 67996

Other (OTH) AF: 0.156 AC: 330 AN: 2112

Alfa AF: 0.185 Hom.: 9704

Bravo AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:3

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.5
DANN	Benign	0.73
PhyloP100		-0.12
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: rs2274623; hg19: chr1-179520108;