rs73928330

Variant names:

• chr19-35851795-C-G
• rs73928330
• NM_004646.4:c.43G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004646.4(NPHS1):​c.43G>C​(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000816 in 1,553,412 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.393
• Publications: 1 publications found

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0106295645).
• BP6: Variant 19-35851795-C-G is Benign according to our data. Variant chr19-35851795-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259502.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00431 (657/152266) while in subpopulation AFR AF = 0.0144 (598/41556). AF 95% confidence interval is 0.0134. There are 1 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004646.4. 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
	NPHS1	NM_004646.4	MANE Select	c.43G>C	p.Gly15Arg	missense	Exon 1 of 29	NP_004637.1	O60500-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.43G>C	p.Gly15Arg	missense	Exon 1 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.43G>C	p.Gly15Arg	missense	Exon 1 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.43G>C	p.Gly15Arg	missense	Exon 1 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000941 AC: 147 AN: 156240 AF XY: 0.000704

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000483

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000505

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000435 AC: 610 AN: 1401146 Hom.: 6 Cov.: 34 AF XY: 0.000359 AC XY: 248 AN XY: 691282

African (AFR) AF: 0.0154 AC: 488 AN: 31728

American (AMR) AF: 0.000866 AC: 31 AN: 35792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 35960

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49412

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5644

European-Non Finnish (NFE) AF: 0.0000250 AC: 27 AN: 1080002

Other (OTH) AF: 0.00105 AC: 61 AN: 58066

GnomAD4 genome AF: 0.00431 AC: 657 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74450

African (AFR) AF: 0.0144 AC: 598 AN: 41556

American (AMR) AF: 0.00334 AC: 51 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.00509

ESP6500AA AF: 0.0109 AC: 47

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000834 AC: 88

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Finnish congenital nephrotic syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.39
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.34
MutPred		0.75		Gain of MoRF binding (P = 0.0519)
MVP		0.72
MPC		0.20
ClinPred		0.014	T
GERP RS		1.4
PromoterAI		0.053	Neutral
Varity_R		0.23
gMVP		0.70
Mutation Taster		=98/2	polymorphism

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: rs73928330; hg19: chr19-36342697;