1-119743954-T-C

Variant names:

• chr1-119743954-T-C
• rs1801955
• NM_006623.4:c.1516T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006623.4(PHGDH):​c.1516T>C​(p.Trp506Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006623.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	NM_006623.4	MANE Select	c.1516T>C	p.Trp506Arg	missense	Exon 12 of 12	NP_006614.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	ENST00000641023.2	MANE Select	c.1516T>C	p.Trp506Arg	missense	Exon 12 of 12	ENSP00000493175.1
	PHGDH	ENST00000369409.9	TSL:1	c.1535T>C	p.Leu512Pro	missense	Exon 12 of 12	ENSP00000358417.5
	PHGDH	ENST00000641597.1		c.1516T>C	p.Trp506Arg	missense	Exon 15 of 15	ENSP00000493382.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111618

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.74	D
PhyloP100		4.2
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.78
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1801955; hg19: chr1-120286577;