rs776977023

Positions:

• chr1-119727097-A-G
• chr1-119727097-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006623.4(PHGDH):​c.505A>G​(p.Met169Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.33

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.505A>G	p.Met169Val	missense_variant	5/12	ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.505A>G	p.Met169Val	missense_variant	5/12		NM_006623.4	ENSP00000493175	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435384 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 715698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;D;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.91
Sift	Benign	0.046	.;.;.;.;.;.;D;.
Sift4G	Benign	0.063	.;.;.;.;.;.;T;.
Polyphen		1.0	D;.;D;.;.;.;.;.
Vest4		0.69
MutPred		0.82		Gain of methylation at K170 (P = 0.025);.;Gain of methylation at K170 (P = 0.025);Gain of methylation at K170 (P = 0.025);Gain of methylation at K170 (P = 0.025);Gain of methylation at K170 (P = 0.025);Gain of methylation at K170 (P = 0.025);.;
MVP		0.89
MPC		0.84
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.85
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776977023; hg19: chr1-120269720;