rs543703

chr1-119742923-G-Achr1-119742923-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. T442T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (37609 hom., cov: 34)
  • Exomes 𝑓: 0.68 (338873 hom.)
• Consequence: PHGDH NM_006623.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.91

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]

ACMG classification

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	UniProt
PHGDH	NM_006623.4	c.1326G>A	p.Thr442=	synonymous_variant	11/12	ENST00000641023.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106465 AN: 152080 Hom.: 37558 Cov.: 34

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

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.: 42 AF XY: 0.684 AC XY: 496867 AN XY: 726846

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.: 34 AF XY: 0.699 AC XY: 51987 AN XY: 74402

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

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	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -

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	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	9.6e-7	T
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

Other links and lift over

dbSNP: rs543703; hg19: chr1-120285546; COSMIC: COSV65570693;