rs758100382
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001930.4(DHPS):āc.518A>Gā(p.Asn173Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_001930.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHPS | NM_001930.4 | c.518A>G | p.Asn173Ser | missense_variant | Exon 4 of 9 | ENST00000210060.12 | NP_001921.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHPS | ENST00000210060.12 | c.518A>G | p.Asn173Ser | missense_variant | Exon 4 of 9 | 1 | NM_001930.4 | ENSP00000210060.6 | ||
ENSG00000285589 | ENST00000648033.1 | n.*63A>G | non_coding_transcript_exon_variant | Exon 4 of 14 | ENSP00000498000.1 | |||||
ENSG00000285589 | ENST00000648033.1 | n.*63A>G | 3_prime_UTR_variant | Exon 4 of 14 | ENSP00000498000.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251482Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135916
GnomAD4 exome AF: 0.0000992 AC: 145AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 76AN XY: 727242
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74336
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with seizures and speech and walking impairment Pathogenic:4
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with seizures and speech and walking impairment, (MIM#618480). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated deoxyhypusine synthase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic three times (ClinVar) and in five affected individuals from four unrelated families who were compound heterozygous for this variant (PMID: 30661771). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cell lines with the p.(Asn173Ser) variant demonstrated only partial enzyme activity, approximately 20% of wild type enzymatic activity (PMID:30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.1014+1G>A) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM3, PS3-Moderate. -
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The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental disorder from four unrelated families (Ganapathi et al. 2019). The p.Asn173Ser variant is reported at a frequency of 0.000116 in the European (non-Finnish) population in the Genome Aggregation Database (version 2.1.1). Functional studies demonstrate that the p.(Asn173Ser) variant exhibited partial enzymatic activity, ranging from 18% to 25% of that of wild-type DHPS resulting in impaired biosynthesis of deoxyhypusine (Ganapathi et al. 2019). Based on the collective evidence the c.518A>G (p.Asn173Ser) variant is classified as pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment. -
DHPS-related disorder Pathogenic:1
The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans with a predicted loss-of-function variant, in all five affected individuals described in the DHPS index study (Ganapathi et al 2019. PubMed ID: 30661771). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12790510-T-C). This variant is interpreted as pathogenic. -
not provided Pathogenic:1
In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30661771, 34273022) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at