1-119734718-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006623.4(PHGDH):c.595C>G(p.Leu199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,162 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L199L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (9 hom.)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.90

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=0.009389281).
• BP6: Variant 1-119734718-C-G is Benign according to our data. Variant chr1-119734718-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 536421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119734718-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00572 (872/152328) while in subpopulation AFR AF= 0.0202 (838/41580). AF 95% confidence interval is 0.019. There are 13 homozygotes in gnomad4. There are 430 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHGDH	NM_006623.4	c.595C>G	p.Leu199Val	missense_variant	6/12	ENST00000641023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.595C>G	p.Leu199Val	missense_variant	6/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152210 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00148 AC: 373 AN: 251486 Hom.: 7 AF XY: 0.00112 AC XY: 152 AN XY: 135918

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1461834 Hom.: 9 Cov.: 31 AF XY: 0.000505 AC XY: 367 AN XY: 727218

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00572 AC: 872 AN: 152328 Hom.: 13 Cov.: 33 AF XY: 0.00577 AC XY: 430 AN XY: 74498

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00645

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2018	- -

Neu-Laxova syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

PHGDH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Benign	0.76
DEOGEN2	Uncertain	0.47	T;T;.;.;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;.;.;.;.;.
MutationTaster	Benign	0.69	D;D
PrimateAI	Benign	0.28	T
Polyphen		0.0010	B;B;.;.;.;.;.
Vest4		0.13
MVP		0.62
MPC		0.26
ClinPred		0.016	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.54

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: rs77632964; hg19: chr1-120277341;