NM_004646.4:c.*457A>G

Variant names:

• chr19-35826057-T-C
• rs113978942
• NM_004646.4:c.*457A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.*457A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 177,904 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (121 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (1 hom.)
• Consequence: NPHS1 NM_004646.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.812
• 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-35826057-T-C is Benign according to our data. Variant chr19-35826057-T-C is described in ClinVar as Benign. ClinVar VariationId is 891941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

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.*457A>G		3_prime_UTR	Exon 29 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.*457A>G		3_prime_UTR	Exon 29 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.*457A>G		3_prime_UTR	Exon 29 of 29	ENSP00000539165.1
	NPHS1	ENST00000869107.1		c.*457A>G		3_prime_UTR	Exon 27 of 27	ENSP00000539166.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3379 AN: 152124 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

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: 0.000235

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00304 AC: 78 AN: 25662 Hom.: 1 Cov.: 0 AF XY: 0.00306 AC XY: 41 AN XY: 13402

African (AFR) AF: 0.0665 AC: 58 AN: 872

American (AMR) AF: 0.00418 AC: 13 AN: 3108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 494

East Asian (EAS) AF: 0.00 AC: 0 AN: 2204

South Asian (SAS) AF: 0.00 AC: 0 AN: 3094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.000144 AC: 2 AN: 13846

Other (OTH) AF: 0.00430 AC: 5 AN: 1162

GnomAD4 genome AF: 0.0223 AC: 3390 AN: 152242 Hom.: 121 Cov.: 32 AF XY: 0.0217 AC XY: 1619 AN XY: 74450

African (AFR) AF: 0.0778 AC: 3232 AN: 41530

American (AMR) AF: 0.00746 AC: 114 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68024

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00265 Hom.: 1

Bravo AF: 0.0252

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital nephrotic syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.7
DANN	Benign	0.30
PhyloP100		-0.81
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: rs113978942; hg19: chr19-36316959;