1-119735394-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_006623.4(PHGDH):c.743C>T(p.Ala248Val) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,614,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A248D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.67

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

neurometabolic disorder due to serine deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
PHGDH deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
Neu-Laxova syndrome 1
Inheritance: AR Classification: MODERATE Submitted by: G2P
Neu-Laxova syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PHGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.02575615).

BP6

Variant 1-119735394-C-T is Benign according to our data. Variant chr1-119735394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 729954.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152350) while in subpopulation EAS AF = 0.00347 (18/5186). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHGDH	NM_006623.4 link	c.743C>T	p.Ala248Val	missense_variant	Exon 7 of 12	ENST00000641023.2	NP_006614.2	O43175

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2 link	c.743C>T	p.Ala248Val	missense_variant	Exon 7 of 12		NM_006623.4	ENSP00000493175.1		O43175

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00346

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000412

AC:

103

AN:

250070

AF XY:

0.000429

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00489

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000246

AC:

359

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00418

AC:

166

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000142

AC:

158

AN:

1112004

Other (OTH)

AF:

0.000315

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00347

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000611

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PHGDH deficiency

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 07, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neu-Laxova syndrome 1

Uncertain:1

Sep 05, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously as a likely pathogenic variant in a patient with West syndrome who also harbored a second variant (phase unknown) (PMID: 34055682); Reported previously as a maternally inherited heterozygous variant in a patient with CAKUT; however, no second variant was identified (PMID: 35711925); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34055682, 35711925) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

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

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.026

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

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

2.9

M;M;.;.;.;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.78

MVP

0.94

MPC

0.81

ClinPred

0.19

GERP RS

4.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.86

gMVP

0.79

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over