chr1-119737114-G-A

Variant names:

• chr1-119737114-G-A
• rs587777774
• NM_006623.4:c.793G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_006623.4(PHGDH):​c.793G>A​(p.Glu265Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E265E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHGDH NM_006623.4 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurometabolic disorder due to serine deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• PHGDH deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Neu-Laxova syndrome 1

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• Neu-Laxova syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006623.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 1-119737114-G-A is Pathogenic according to our data. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-119737114-G-A is described in CliVar as Pathogenic. Clinvar id is 156360.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.793G>A	p.Glu265Lys	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.793G>A	p.Glu265Lys	missense_variant, splice_region_variant	Exon 8 of 12		NM_006623.4	ENSP00000493175.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251156 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neu-Laxova syndrome 1 Pathogenic:1

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	.;.;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.72
MutPred		0.84		Gain of methylation at E265 (P = 0.0024);Gain of methylation at E265 (P = 0.0024);Gain of methylation at E265 (P = 0.0024);Gain of methylation at E265 (P = 0.0024);Gain of methylation at E265 (P = 0.0024);Gain of methylation at E265 (P = 0.0024);
MVP		0.96
MPC		0.63
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.95
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777774; hg19: chr1-120279737;