rs3818587

Variant names:

• chr1-179551287-T-C
• rs3818587
• NM_014625.4:c.1038A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014625.4(NPHS2):​c.1038A>G​(p.Leu346Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,613,852 control chromosomes in the GnomAD database, including 6,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (610 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5719 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0750
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-179551287-T-C is Benign according to our data. Variant chr1-179551287-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.1038A>G	p.Leu346Leu	synonymous	Exon 8 of 8	NP_055440.1
	AXDND1	NM_144696.6	MANE Select	c.3032-3225T>C		intron	N/A	NP_653297.3
	NPHS2	NM_001297575.2		c.834A>G	p.Leu278Leu	synonymous	Exon 7 of 7	NP_001284504.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.1038A>G	p.Leu346Leu	synonymous	Exon 8 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.834A>G	p.Leu278Leu	synonymous	Exon 7 of 7	ENSP00000356588.4
	AXDND1	ENST00000367618.8	TSL:1 MANE Select	c.3032-3225T>C		intron	N/A	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12833 AN: 151884 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.0796

GnomAD2 exomes AF: 0.0735 AC: 18453 AN: 251196 AF XY: 0.0706

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.0938

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.0767

GnomAD4 exome AF: 0.0845 AC: 123590 AN: 1461850 Hom.: 5719 Cov.: 46 AF XY: 0.0818 AC XY: 59517 AN XY: 727226

African (AFR) AF: 0.0860 AC: 2878 AN: 33480

American (AMR) AF: 0.0376 AC: 1681 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 1686 AN: 26132

East Asian (EAS) AF: 0.0673 AC: 2673 AN: 39700

South Asian (SAS) AF: 0.0137 AC: 1182 AN: 86258

European-Finnish (FIN) AF: 0.131 AC: 6988 AN: 53420

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5766

European-Non Finnish (NFE) AF: 0.0912 AC: 101403 AN: 1111980

Other (OTH) AF: 0.0831 AC: 5019 AN: 60394

GnomAD4 genome AF: 0.0845 AC: 12841 AN: 152002 Hom.: 610 Cov.: 32 AF XY: 0.0837 AC XY: 6218 AN XY: 74304

African (AFR) AF: 0.0891 AC: 3694 AN: 41444

American (AMR) AF: 0.0593 AC: 905 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 259 AN: 3472

East Asian (EAS) AF: 0.0890 AC: 459 AN: 5158

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4810

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10584

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0854 AC: 5802 AN: 67966

Other (OTH) AF: 0.0792 AC: 167 AN: 2108

Alfa AF: 0.0803 Hom.: 886

Bravo AF: 0.0800

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0768

EpiControl AF: 0.0756

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nephrotic syndrome, type 2 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.0
DANN	Benign	0.55
PhyloP100		-0.075
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: rs3818587; hg19: chr1-179520422; COSMIC: COSV62635449; COSMIC: COSV62635449;