NM_004646.4:c.563A>T

Variant names:

• chr19-35850409-T-A
• rs145125791
• NM_004646.4:c.563A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004646.4(NPHS1):​c.563A>T​(p.Asn188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,614,106 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (66 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.514
• Publications: 12 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]

NPHS1 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025585592).
• BP6: Variant 19-35850409-T-A is Benign according to our data. Variant chr19-35850409-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282372.
• BS2: High Homozygotes in GnomAd4 at 3 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.563A>T	p.Asn188Ile	missense	Exon 5 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.563A>T	p.Asn188Ile	missense	Exon 5 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.563A>T	p.Asn188Ile	missense	Exon 5 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.563A>T	p.Asn188Ile	missense	Exon 5 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 915 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00605 AC: 1521 AN: 251492 AF XY: 0.00636

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00820 AC: 11985 AN: 1461836 Hom.: 66 Cov.: 31 AF XY: 0.00806 AC XY: 5865 AN XY: 727226

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00487 AC: 218 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00539 AC: 465 AN: 86258

European-Finnish (FIN) AF: 0.00311 AC: 166 AN: 53412

Middle Eastern (MID) AF: 0.00989 AC: 57 AN: 5766

European-Non Finnish (NFE) AF: 0.00945 AC: 10503 AN: 1111970

Other (OTH) AF: 0.00782 AC: 472 AN: 60390

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74448

African (AFR) AF: 0.00178 AC: 74 AN: 41542

American (AMR) AF: 0.00726 AC: 111 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

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

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4818

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00956 AC: 650 AN: 68018

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00837 Hom.: 1

Bravo AF: 0.00631

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Finnish congenital nephrotic syndrome (5)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	1	-	Congenital nephrotic syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	NPHS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.51
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.25
Sift	Benign	0.56	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.57	P
Vest4		0.79
MVP		0.83
MPC		0.44
ClinPred		0.0048	T
GERP RS		2.2
Varity_R		0.22
gMVP		0.53
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.060		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: rs145125791; hg19: chr19-36341311; COSMIC: COSV105273982; COSMIC: COSV105273982;