1-119712024-T-C

Variant names:

• chr1-119712024-T-C
• rs951372478
• NM_006623.4:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_006623.4(PHGDH):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHGDH NM_006623.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.00

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]

LOC105378937 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 96 codons. Genomic position: 119721317. Lost 0.179 part of the original CDS.
• PS1: Another start lost variant in NM_006623.4 (PHGDH) was described as [Pathogenic] in ClinVar as 2169478
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119712024-T-C is Pathogenic according to our data. Variant chr1-119712024-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1331415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 12	ENST00000641023.2	NP_006614.2
PHGDH	XM_011541226.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 14		XP_011539528.1
PHGDH	XR_007058634.1	n.91T>C		non_coding_transcript_exon_variant	Exon 1 of 8
LOC105378937	XR_947757.4	n.-178A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 12		NM_006623.4	ENSP00000493175.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Pathogenic:3

Feb 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1331415). 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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PHGDH c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next alternative downstream in-frame start codon (Met 96) is located at the end of exon 2. Therefore, a severe outcome is predicted. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251114 control chromosomes. To our knowledge, no occurrence of c.2T>C in individuals affected with Phosphoglycerate Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. However, the HGMD database lists at-least one other variant resulting in the same translational impact, namely c.1A>C (p.M1?) that has been associated with a phenotype of Neu-Laxova syndrome, an allelic autosomal recessive disorder with a more severe phenotype that usually results in neonatal death. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Neu-Laxova syndrome 1 Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;D;.;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
PROVEAN	Uncertain	-2.5	.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;D;.
Polyphen		0.99	D;.;D;.;.;.;.;.
Vest4		0.92
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);Gain of catalytic residue at M1 (P = 0.0157);
MVP		0.96
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.89
gMVP		0.51

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

Other links and lift over

dbSNP: rs951372478; hg19: chr1-120254647;