1-119734718-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006623.4(PHGDH):c.595C>T(p.Leu199Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L199V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38163123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHGDH	NM_006623.4	c.595C>T	p.Leu199Phe	missense_variant	6/12	ENST00000641023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.595C>T	p.Leu199Phe	missense_variant	6/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;.;.;.;.;.
Eigen	Benign	0.032
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.72	N;N;.;.;.;.;.
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.31	T
Polyphen		0.65	P;P;.;.;.;.;.
Vest4		0.25
MutPred		0.43		Loss of catalytic residue at L199 (P = 0.1177);Loss of catalytic residue at L199 (P = 0.1177);Loss of catalytic residue at L199 (P = 0.1177);Loss of catalytic residue at L199 (P = 0.1177);Loss of catalytic residue at L199 (P = 0.1177);Loss of catalytic residue at L199 (P = 0.1177);.;
MVP		0.78
MPC		0.48
ClinPred		0.68	D
GERP RS		3.4
Varity_R		0.53
gMVP		0.50

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; COSMIC: COSV65570953; COSMIC: COSV65570953;