rs543703

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006623.4(PHGDH):c.1326G>A(p.Thr442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,613,196 control chromosomes in the GnomAD database, including 376,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37609 hom., cov: 34)

Exomes 𝑓: 0.68 ( 338873 hom. )

Consequence

PHGDH
NM_006623.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.91

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.60891E-7).

BP6

Variant 1-119742923-G-A is Benign according to our data. Variant chr1-119742923-G-A is described in ClinVar as [Benign]. Clinvar id is 292321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119742923-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHGDH	NM_006623.4 linkuse as main transcript	c.1326G>A	p.Thr442=	synonymous_variant	11/12	ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2 linkuse as main transcript	c.1326G>A	p.Thr442=	synonymous_variant	11/12		NM_006623.4	ENSP00000493175	P1

Frequencies

GnomAD3 genomes

AF:

0.700

AC:

106465

AN:

152080

Hom.:

37558

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.601

Gnomad AMR

AF:

0.730

Gnomad ASJ

AF:

0.789

Gnomad EAS

AF:

0.603

Gnomad SAS

AF:

0.798

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.727

GnomAD3 exomes

AF:

0.691

AC:

173491

AN:

251152

Hom.:

60716

AF XY:

0.699

AC XY:

94864

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.754

Gnomad AMR exome

AF:

0.686

Gnomad ASJ exome

AF:

0.795

Gnomad EAS exome

AF:

0.605

Gnomad SAS exome

AF:

0.804

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.679

Gnomad OTH exome

AF:

0.699

GnomAD4 exome

AF:

0.679

AC:

991360

AN:

1460998

Hom.:

338873

Cov.:

AF XY:

0.684

AC XY:

496867

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.754

Gnomad4 AMR exome

AF:

0.691

Gnomad4 ASJ exome

AF:

0.794

Gnomad4 EAS exome

AF:

0.596

Gnomad4 SAS exome

AF:

0.804

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.670

Gnomad4 OTH exome

AF:

0.684

GnomAD4 genome

AF:

0.700

AC:

106559

AN:

152198

Hom.:

37609

Cov.:

AF XY:

0.699

AC XY:

51987

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.758

Gnomad4 AMR

AF:

0.729

Gnomad4 ASJ

AF:

0.789

Gnomad4 EAS

AF:

0.603

Gnomad4 SAS

AF:

0.798

Gnomad4 FIN

AF:

0.573

Gnomad4 NFE

AF:

0.674

Gnomad4 OTH

AF:

0.722

Alfa

AF:

0.690

Hom.:

71143

Bravo

AF:

0.712

TwinsUK

AF:

0.659

AC:

2444

ALSPAC

AF:

0.676

AC:

2607

ESP6500AA

AF:

0.752

AC:

3313

ESP6500EA

AF:

0.683

AC:

5870

ExAC

AF:

0.692

AC:

83997

Asia WGS

AF:

0.678

AC:

2358

AN:

3478

EpiCase

AF:

0.699

EpiControl

AF:

0.710

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PHGDH deficiency

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2016	Variant summary: The c.1326G>A (p.Thr142=) in PHGDH gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 0.69 (83957/121254 chrs tested), which exceeds the estimated maximal expected allele frequency of a pathogenic variant in this gene. The c.1326G>A has not, to our knowledge, been reported in affected individuals via published reports or cited by a reputable database/clinical laboratory. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Neu-Laxova syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.27

DANN

Benign

0.37

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.28

MetaRNN

Benign

9.6e-7

MutationTaster

Benign

0.00012

P;P

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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