chr1-119712023-A-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_006623.4(PHGDH):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PHGDH
NM_006623.4 start_lost
NM_006623.4 start_lost
Scores
4
3
4
Clinical Significance
Conservation
PhyloP100: 8.14
Genes affected
PHGDH (HGNC:8923): (phosphoglycerate dehydrogenase) This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_006623.4 (PHGDH) was described as [Likely_pathogenic] in ClinVar as 1331415
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-119712023-A-C is Pathogenic according to our data. Variant chr1-119712023-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2169478.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHGDH | NM_006623.4 | c.1A>C | p.Met1? | start_lost | 1/12 | ENST00000641023.2 | |
PHGDH | XM_011541226.3 | c.1A>C | p.Met1? | start_lost | 1/14 | ||
PHGDH | XR_007058634.1 | n.90A>C | non_coding_transcript_exon_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHGDH | ENST00000641023.2 | c.1A>C | p.Met1? | start_lost | 1/12 | NM_006623.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727176
GnomAD4 exome
AF:
AC:
3
AN:
1461746
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727176
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
PHGDH deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 01, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2169478). Disruption of the initiator codon has been observed in individual(s) with Neu-Laxova syndrome (PMID: 30838783). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PHGDH mRNA. The next in-frame methionine is located at codon 96. - |
Neu-Laxova syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 27, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Uncertain
D;.;D;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D
Polyphen
P;.;P;.;.;.;.;.
Vest4
0.92
MutPred
Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);
MVP
0.86
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.