chr19-35846016-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_004646.4(NPHS1):c.1619C>A(p.Ala540Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,422,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 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. A540A) has been classified as Likely benign.
Frequency
Consequence
NM_004646.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.1619C>A | p.Ala540Glu | missense_variant | 12/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.1619C>A | p.Ala540Glu | missense_variant | 12/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.1619C>A | p.Ala540Glu | missense_variant | 12/28 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000492 AC: 72AN: 146490Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000323 AC: 63AN: 194768Hom.: 0 AF XY: 0.000295 AC XY: 31AN XY: 104982
GnomAD4 exome AF: 0.00101 AC: 1283AN: 1275776Hom.: 1 Cov.: 38 AF XY: 0.000895 AC XY: 565AN XY: 631044
GnomAD4 genome AF: 0.000492 AC: 72AN: 146490Hom.: 0 Cov.: 32 AF XY: 0.000448 AC XY: 32AN XY: 71472
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 22, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
NPHS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2024 | The NPHS1 c.1619C>A variant is predicted to result in the amino acid substitution p.Ala540Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Finnish congenital nephrotic syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 05, 2019 | - - |
Congenital nephrotic syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at