Variant chr1-119712023-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_006623.4(PHGDH):c.1A>C(p.Met1?) variant causes a start lost 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 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.14

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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-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_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PHGDH	NM_006623.4 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/12	ENST00000641023.2
PHGDH	XM_011541226.3 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/14
PHGDH	XR_007058634.1 linkuse as main transcript	n.90A>C		non_coding_transcript_exon_variant	1/8

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727176

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PHGDH deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2169478). 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. -

Neu-Laxova syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.51

D;.;D;.;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over