NM_006623.4:c.1468G>A

Variant names:

• chr1-119743906-G-A
• rs121907987
• NM_006623.4:c.1468G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_006623.4(PHGDH):​c.1468G>A​(p.Val490Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000698713: functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002).; SCV000951673: Experimental studies have shown that this missense change affects PHGDH function (PMID:11055895, 11751922).; SCV001984849: Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID:11055895, 11751922).; SCV005418301: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005329503: Experimental studies show that the variant results in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp LW, et al., 2000, Pind S, et al., 2002).". Synonymous variant affecting the same amino acid position (i.e. V490V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 2.14
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• neurometabolic disorder due to serine deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• PHGDH deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Neu-Laxova syndrome 1

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• Neu-Laxova syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000698713: functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002).; SCV000951673: Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922).; SCV001984849: Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922).; SCV005418301: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005329503: Experimental studies show that the variant results in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp LW, et al., 2000, Pind S, et al., 2002).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119743906-G-A is Pathogenic according to our data. Variant chr1-119743906-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006623.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	NM_006623.4	MANE Select	c.1468G>A	p.Val490Met	missense	Exon 12 of 12	NP_006614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	ENST00000641023.2	MANE Select	c.1468G>A	p.Val490Met	missense	Exon 12 of 12	ENSP00000493175.1	O43175
	PHGDH	ENST00000369409.9	TSL:1	c.1487G>A	p.Arg496His	missense	Exon 12 of 12	ENSP00000358417.5	A0A2C9F2M7
	PHGDH	ENST00000641597.1		c.1468G>A	p.Val490Met	missense	Exon 15 of 15	ENSP00000493382.1	O43175

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249930 AF XY: 0.000118

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.0000713

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461510 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727084

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111712

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	PHGDH deficiency (8)
2	-	-	Neu-Laxova syndrome 1 (2)
2	-	-	PHGDH deficiency;C4551478:Neu-Laxova syndrome 1 (2)
1	-	-	not provided (1)
1	-	-	PHGDH-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.10
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.46	T
PhyloP100		2.1
ClinPred		0.091	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121907987; hg19: chr1-120286529; COSMIC: COSV65569643; COSMIC: COSV65569643;