1-119712046-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006623.4(PHGDH):c.24A>T(p.Lys8Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHGDH	NM_006623.4	c.24A>T	p.Lys8Asn	missense_variant	1/12	ENST00000641023.2
PHGDH	XM_011541226.3	c.24A>T	p.Lys8Asn	missense_variant	1/14
PHGDH	XR_007058634.1	n.113A>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641023.2	c.24A>T	p.Lys8Asn	missense_variant	1/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Invitae

Nov 27, 2021

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 8 of the PHGDH protein (p.Lys8Asn). This variant is not present in population databases (gnomAD 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	0.53
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;D;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
Polyphen		0.19	B;.;B;.;.;.;.;.
Vest4		0.49
MutPred		0.61		Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);Loss of methylation at K8 (P = 0.0132);
MVP		0.97
MPC		0.33
ClinPred		0.85	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-120254669;