rs386833934

Variant names:

• chr19-35851339-G-A
• rs386833934
• NM_004646.4:c.320C>T
• NPHS1 p.Ala107Val

Your query was ambiguous. Multiple possible variants found:

• chr19-35851339-G-A
• chr19-35851339-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_004646.4(NPHS1):​c.320C>T​(p.Ala107Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A107T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 3.78
• Publications: 6 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004646.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35851340-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56494.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

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.320C>T	p.Ala107Val	missense	Exon 3 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.320C>T	p.Ala107Val	missense	Exon 3 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.320C>T	p.Ala107Val	missense	Exon 3 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.320C>T	p.Ala107Val	missense	Exon 3 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249102 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461458 Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000914 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	3	-	Finnish congenital nephrotic syndrome (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
PromoterAI		0.078	Neutral
Varity_R		0.67
gMVP		0.82
Mutation Taster		=10/90	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs386833934;

hg19: chr19-36342241;