rs77632964

Variant names:

• chr1-119734718-C-G
• rs77632964
• NM_006623.4:c.595C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-119734718-C-G
• chr1-119734718-C-A
• chr1-119734718-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006623.4(PHGDH):​c.595C>G​(p.Leu199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,162 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L199L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (9 hom.)
• Consequence: PHGDH NM_006623.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.90
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009389281).
• BP6: Variant 1-119734718-C-G is Benign according to our data. Variant chr1-119734718-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 536421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00572 (872/152328) while in subpopulation AFR AF = 0.0202 (838/41580). AF 95% confidence interval is 0.019. There are 13 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	NM_006623.4	MANE Select	c.595C>G	p.Leu199Val	missense	Exon 6 of 12	NP_006614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	ENST00000641023.2	MANE Select	c.595C>G	p.Leu199Val	missense	Exon 6 of 12	ENSP00000493175.1	O43175
	PHGDH	ENST00000369409.9	TSL:1	c.595C>G	p.Leu199Val	missense	Exon 6 of 12	ENSP00000358417.5	A0A2C9F2M7
	PHGDH	ENST00000641597.1		c.595C>G	p.Leu199Val	missense	Exon 9 of 15	ENSP00000493382.1	O43175

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152210 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00148 AC: 373 AN: 251486 AF XY: 0.00112

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1461834 Hom.: 9 Cov.: 31 AF XY: 0.000505 AC XY: 367 AN XY: 727218

African (AFR) AF: 0.0230 AC: 771 AN: 33462

American (AMR) AF: 0.000604 AC: 27 AN: 44724

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

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111976

Other (OTH) AF: 0.00114 AC: 69 AN: 60394

GnomAD4 genome AF: 0.00572 AC: 872 AN: 152328 Hom.: 13 Cov.: 33 AF XY: 0.00577 AC XY: 430 AN XY: 74498

African (AFR) AF: 0.0202 AC: 838 AN: 41580

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00645

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	PHGDH deficiency (3)
-	-	2	not provided (2)
-	-	1	Neu-Laxova syndrome 1 (1)
-	-	1	PHGDH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.16	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.62
MPC		0.26
ClinPred		0.016	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.54
Mutation Taster		=87/13	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: rs77632964; hg19: chr1-120277341;