1-119712042-G-C

Position:

• chr1-119712042-G-C

Variant summary

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

The NM_006623.4(PHGDH):​c.20G>C​(p.Arg7Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R7R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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=0.41847235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHGDH	NM_006623.4	c.20G>C	p.Arg7Pro	missense_variant	1/12	ENST00000641023.2
PHGDH	XM_011541226.3	c.20G>C	p.Arg7Pro	missense_variant	1/14
PHGDH	XR_007058634.1	n.109G>C		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.20G>C	p.Arg7Pro	missense_variant	1/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PHGDH deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces arginine with proline at codon 7 of the PHGDH protein (p.Arg7Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PHGDH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;.;D;.;.;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;.;L;.;.;.;.;.
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	.;.;.;.;.;.;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0090	.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.030	.;.;.;.;.;.;D;.
Polyphen		0.10	B;.;B;.;.;.;.;.
Vest4		0.38
MutPred		0.63		Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);
MVP		0.84
MPC		0.47
ClinPred		0.89	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.62

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: rs1650717022; hg19: chr1-120254665;