rs543703

Variant names:

• chr1-119742923-G-A
• rs543703
• NM_006623.4:c.1326G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-119742923-G-A
• chr1-119742923-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006623.4(PHGDH):​c.1326G>A​(p.Thr442Thr) 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:11
• Conservation: PhyloP100: -4.91
• Publications: 27 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 292321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.1326G>A	p.Thr442Thr	synonymous_variant	Exon 11 of 12	ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.1326G>A	p.Thr442Thr	synonymous_variant	Exon 11 of 12		NM_006623.4	ENSP00000493175.1

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

GnomAD2 exomes AF: 0.691 AC: 173491 AN: 251152 AF XY: 0.699

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 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

African (AFR) AF: 0.754 AC: 25221 AN: 33466

American (AMR) AF: 0.691 AC: 30892 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 20742 AN: 26136

East Asian (EAS) AF: 0.596 AC: 23651 AN: 39690

South Asian (SAS) AF: 0.804 AC: 69364 AN: 86246

European-Finnish (FIN) AF: 0.579 AC: 30926 AN: 53414

Middle Eastern (MID) AF: 0.823 AC: 4743 AN: 5764

European-Non Finnish (NFE) AF: 0.670 AC: 744552 AN: 1111202

Other (OTH) AF: 0.684 AC: 41269 AN: 60360

GnomAD4 genome AF: 0.700 AC: 106559 AN: 152198 Hom.: 37609 Cov.: 34 AF XY: 0.699 AC XY: 51987 AN XY: 74402

African (AFR) AF: 0.758 AC: 31481 AN: 41544

American (AMR) AF: 0.729 AC: 11161 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2741 AN: 3472

East Asian (EAS) AF: 0.603 AC: 3105 AN: 5152

South Asian (SAS) AF: 0.798 AC: 3857 AN: 4832

European-Finnish (FIN) AF: 0.573 AC: 6066 AN: 10586

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45836 AN: 67994

Other (OTH) AF: 0.722 AC: 1524 AN: 2112

Alfa AF: 0.688 Hom.: 149901

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

Submissions by phenotype

PHGDH deficiency Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Mar 30, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neu-Laxova syndrome 1 Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
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
PhyloP100		-4.9
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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