chr1-119726868-C-T

Position:

chr1-119726868-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_006623.4(PHGDH):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 1.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-119726868-C-T is Pathogenic according to our data. Variant chr1-119726868-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373899.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr1-119726868-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2855714). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHGDH	NM_006623.4 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant	4/12	ENST00000641023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant	4/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251482

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PHGDH deficiency

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the PHGDH protein (p.Thr125Met). This variant is present in population databases (rs764618040, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of PHGDH-related conditions (PMID: 29286531). ClinVar contains an entry for this variant (Variation ID: 373899). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHGDH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. -

Seizure;C0543888:Epileptic encephalopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 11, 2014

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2022

The c.374C>T (p.T125M) alteration is located in exon 4 (coding exon 4) of the PHGDH gene. This alteration results from a C to T substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

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

Eigen

Benign

0.045

Eigen_PC

Benign

0.00072

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.92

.;D;T;D;D;D;T;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.20

N;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

.;.;.;.;.;.;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.12

.;.;.;.;.;.;T;.

Sift4G

Benign

0.22

.;.;.;.;.;.;T;.

Polyphen

0.95

P;.;P;.;.;.;.;.

Vest4

0.31

MutPred

0.56

Gain of MoRF binding (P = 0.079);.;Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);.;

MVP

0.87

MPC

0.51

ClinPred

0.69

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.24

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over