Genetic Variant NM_014625.4:c.890C>A (chr1-179551435-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_014625.4(NPHS2):c.890C>A(p.Ala297Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A297V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.77

Publications

7 publications found

Variant links:

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

NPHS2 links:

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014625.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-179551435-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 370718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHS2	NM_014625.4	MANE Select	c.890C>A	p.Ala297Glu	missense	Exon 8 of 8	NP_055440.1
AXDND1	NM_144696.6	MANE Select	c.3032-3077G>T		intron	N/A	NP_653297.3
NPHS2	NM_001297575.2		c.686C>A	p.Ala229Glu	missense	Exon 7 of 7	NP_001284504.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.890C>A	p.Ala297Glu	missense	Exon 8 of 8	ENSP00000356587.4
NPHS2	ENST00000367616.4	TSL:1	c.686C>A	p.Ala229Glu	missense	Exon 7 of 7	ENSP00000356588.4
AXDND1	ENST00000367618.8	TSL:1 MANE Select	c.3032-3077G>T		intron	N/A	ENSP00000356590.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.069

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.56

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

PhyloP100

4.8

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.48

Vest4

0.42

MutPred

0.69

Loss of MoRF binding (P = 0.0189)

MVP

0.88

MPC

0.55

ClinPred

0.84

GERP RS

5.7

Varity_R

0.65

gMVP

0.94

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over