1-119712023-A-C

Variant names:

• chr1-119712023-A-C
• NM_006623.4:c.1A>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.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,746 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHGDH NM_006623.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

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 [Likely_pathogenic] in ClinVar as 1331415
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119712023-A-C is Pathogenic according to our data. Variant chr1-119712023-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2169478.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.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 12	ENST00000641023.2	NP_006614.2
PHGDH	XM_011541226.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 14		XP_011539528.1
PHGDH	XR_007058634.1	n.90A>C		non_coding_transcript_exon_variant	Exon 1 of 8
LOC105378937	XR_947757.4	n.-177T>G		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Pathogenic:1

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 2169478). For these reasons, this variant has been classified as Pathogenic. -

Neu-Laxova syndrome 1 Pathogenic:1

Feb 27, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PHGDH deficiency;C4551478:Neu-Laxova syndrome 1 Pathogenic:1

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: 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	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Uncertain	0.51	D;.;D;.;.;.;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
PROVEAN	Benign	-1.5	.;.;.;.;.;.;N;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;D;.
Polyphen		0.81	P;.;P;.;.;.;.;.
Vest4		0.92
MutPred		0.99		Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);Loss of MoRF binding (P = 0.1548);
MVP		0.86
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-120254646;