NM_004646.4:c.349G>A

Variant names:

• chr19-35851310-C-T
• rs3814995
• NM_004646.4:c.349G>A

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.349G>A​(p.Glu117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,613,534 control chromosomes in the GnomAD database, including 81,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6489 hom., cov: 31)
  • Exomes 𝑓: 0.31 (75013 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.48
• Publications: 69 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 (MetaRNN=1.4799833E-4).
• BP6: Variant 19-35851310-C-T is Benign according to our data. Variant chr19-35851310-C-T is described in ClinVar as Benign. ClinVar VariationId is 259500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 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.349G>A	p.Glu117Lys	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.349G>A	p.Glu117Lys	missense	Exon 3 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.349G>A	p.Glu117Lys	missense	Exon 3 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.349G>A	p.Glu117Lys	missense	Exon 3 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39879 AN: 151938 Hom.: 6490 Cov.: 31

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.324 AC: 81058 AN: 249994 AF XY: 0.318

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.313 AC: 457173 AN: 1461478 Hom.: 75013 Cov.: 54 AF XY: 0.311 AC XY: 226220 AN XY: 727008

African (AFR) AF: 0.0745 AC: 2494 AN: 33480

American (AMR) AF: 0.410 AC: 18306 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6875 AN: 26136

East Asian (EAS) AF: 0.606 AC: 24046 AN: 39682

South Asian (SAS) AF: 0.236 AC: 20370 AN: 86246

European-Finnish (FIN) AF: 0.356 AC: 19012 AN: 53336

Middle Eastern (MID) AF: 0.207 AC: 1194 AN: 5768

European-Non Finnish (NFE) AF: 0.312 AC: 346472 AN: 1111804

Other (OTH) AF: 0.305 AC: 18404 AN: 60376

GnomAD4 genome AF: 0.262 AC: 39876 AN: 152056 Hom.: 6489 Cov.: 31 AF XY: 0.268 AC XY: 19898 AN XY: 74312

African (AFR) AF: 0.0862 AC: 3581 AN: 41550

American (AMR) AF: 0.332 AC: 5075 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3470

East Asian (EAS) AF: 0.620 AC: 3195 AN: 5154

South Asian (SAS) AF: 0.240 AC: 1156 AN: 4810

European-Finnish (FIN) AF: 0.360 AC: 3801 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21198 AN: 67942

Other (OTH) AF: 0.293 AC: 618 AN: 2112

Alfa AF: 0.293 Hom.: 21222

Bravo AF: 0.259

TwinsUK AF: 0.321 AC: 1191

ALSPAC AF: 0.307 AC: 1185

ESP6500AA AF: 0.0919 AC: 405

ESP6500EA AF: 0.306 AC: 2628

ExAC AF: 0.311 AC: 37806

Asia WGS AF: 0.378 AC: 1313 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.299

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Finnish congenital nephrotic syndrome (5)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.096	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.49
MPC		0.62
ClinPred		0.023	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.64
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3814995; hg19: chr19-36342212; COSMIC: COSV62287878; COSMIC: COSV62287878;