19-35851666-G-T

Variant names:

• chr19-35851666-G-T
• rs116617171
• NM_004646.4:c.65C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004646.4(NPHS1):​c.65C>A​(p.Ala22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 9 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.65C>A	p.Ala22Glu	missense	Exon 2 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.65C>A	p.Ala22Glu	missense	Exon 2 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.65C>A	p.Ala22Glu	missense	Exon 2 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.65C>A	p.Ala22Glu	missense	Exon 2 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 242312 AF XY: 0.00000759

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: 0.0000486

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460094 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726242

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111290

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.81	P
Vest4		0.44
MutPred		0.60		Gain of solvent accessibility (P = 0.0145)
MVP		0.84
MPC		0.20
ClinPred		0.42	T
GERP RS		4.1
PromoterAI		-0.029	Neutral
Varity_R		0.29
gMVP		0.61
Mutation Taster		=71/29	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: rs116617171; hg19: chr19-36342568;