NM_004646.4:c.-170T>C

Variant names:

• chr19-35852007-A-G
• rs401824
• NM_004646.4:c.-170T>C

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.-170T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 149,956 control chromosomes in the GnomAD database, including 4,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.16 (4242 hom., cov: 31)
• Consequence: NPHS1 NM_004646.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.63
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-35852007-A-G is Benign according to our data. Variant chr19-35852007-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 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.-170T>C		5_prime_UTR	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.-170T>C		5_prime_UTR	Exon 1 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.-170T>C		5_prime_UTR	Exon 1 of 29	ENSP00000539165.1
	NPHS1	ENST00000869107.1		c.-170T>C		5_prime_UTR	Exon 1 of 27	ENSP00000539166.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23632 AN: 149864 Hom.: 4213 Cov.: 31

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0647

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 23708 AN: 149956 Hom.: 4242 Cov.: 31 AF XY: 0.155 AC XY: 11351 AN XY: 73030

African (AFR) AF: 0.445 AC: 18252 AN: 41022

American (AMR) AF: 0.0784 AC: 1180 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.0655 AC: 226 AN: 3448

East Asian (EAS) AF: 0.132 AC: 671 AN: 5098

South Asian (SAS) AF: 0.0643 AC: 301 AN: 4682

European-Finnish (FIN) AF: 0.0433 AC: 432 AN: 9968

Middle Eastern (MID) AF: 0.0699 AC: 20 AN: 286

European-Non Finnish (NFE) AF: 0.0347 AC: 2338 AN: 67412

Other (OTH) AF: 0.122 AC: 254 AN: 2074

Alfa AF: 0.131 Hom.: 583

Bravo AF: 0.172

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.55
PhyloP100		-2.6
PromoterAI		0.038	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs401824; hg19: chr19-36342909;