1-119712023-A-G

Position:

• chr1-119712023-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_006623.4(PHGDH):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHGDH NM_006623.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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-G is Pathogenic according to our data. Variant chr1-119712023-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1414498.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>G	p.Met1?	start_lost	1/12	ENST00000641023.2
PHGDH	XM_011541226.3	c.1A>G	p.Met1?	start_lost	1/14
PHGDH	XR_007058634.1	n.90A>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.1A>G	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: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PHGDH deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2023

This sequence change affects the initiator methionine of the PHGDH mRNA. The next in-frame methionine is located at codon 96. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 1414498). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;T;.;.;.;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.9	.;.;.;.;.;.;N;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;D;.
Polyphen		0.21	B;.;B;.;.;.;.;.
Vest4		0.95
MutPred		0.99		Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);Loss of disorder (P = 0.1409);
MVP		0.88
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.87
gMVP		0.55

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: rs1331155296; hg19: chr1-120254646;