1-119712024-T-C

Position:

• chr1-119712024-T-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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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/exons	MANE	UniProt
PHGDH	NM_006623.4	c.2T>C	p.Met1?	start_lost	1/12	ENST00000641023.2
PHGDH	XM_011541226.3	c.2T>C	p.Met1?	start_lost	1/14
PHGDH	XR_007058634.1	n.91T>C		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.2T>C	p.Met1?	start_lost	1/12		NM_006623.4	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1331415). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Neu-Laxova syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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
MutationTaster	Benign	1.0	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;