rs201782441

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006623.4(PHGDH):c.743C>A(p.Ala248Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,748 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A248V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.67

Variant links:

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]

PHGDH links:

PHGDH (HGNC:):

PHGDH links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHGDH	NM_006623.4 linkuse as main transcript	c.743C>A	p.Ala248Asp	missense_variant	7/12	ENST00000641023.2	NP_006614.2	O43175

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2 linkuse as main transcript	c.743C>A	p.Ala248Asp	missense_variant	7/12		NM_006623.4	ENSP00000493175.1		O43175

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250070

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PHGDH deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 09, 2022	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 248 of the PHGDH protein (p.Ala248Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHGDH protein function. ClinVar contains an entry for this variant (Variation ID: 536420). This variant has not been reported in the literature in individuals affected with PHGDH-related conditions. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Neu-Laxova syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2022

The c.743C>A (p.A248D) alteration is located in exon 7 (coding exon 7) of the PHGDH gene. This alteration results from a C to A substitution at nucleotide position 743, causing the alanine (A) at amino acid position 248 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250070) total alleles studied. This alteration was found to be homozygous in a fetus with clinical features of Neu-Laxova syndrome (current proband / Ambry Internal Data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;.;.;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.2

H;H;.;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.3

.;.;.;.;.;D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

.;.;.;.;.;D;.

Sift4G

Uncertain

0.0020

.;.;.;.;.;D;.

Polyphen

1.0

D;D;.;.;.;.;.

Vest4

0.88

MutPred

0.83

Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.99

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over