Variant 1-119712046-A-T details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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
PHGDH	NM_006623.4 linkuse as main transcript	c.24A>T	p.Lys8Asn	missense_variant	1/12	ENST00000641023.2
PHGDH	XM_011541226.3 linkuse as main transcript	c.24A>T	p.Lys8Asn	missense_variant	1/14
PHGDH	XR_007058634.1 linkuse as main transcript	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 linkuse as main transcript	c.24A>T	p.Lys8Asn	missense_variant	1/12		NM_006623.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PHGDH deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.;D;.;.;.;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

.;D;D;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.030

MutationAssessor

Uncertain

2.4

M;.;M;.;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.0

.;.;.;.;.;.;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.16

.;.;.;.;.;.;T;.

Sift4G

Benign

0.19

.;.;.;.;.;.;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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over