rs541503

Variant names:

• chr1-119665674-T-C
• rs541503
• ENST00000641597.1:c.-615-3520T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000641597.1(PHGDH):​c.-615-3520T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 151,884 control chromosomes in the GnomAD database, including 8,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8218 hom., cov: 30)
• Consequence: PHGDH ENST00000641597.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.406
• Publications: 12 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

LOC124904390 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124904390	XR_007066508.1	n.217-3517T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641597.1	c.-615-3520T>C		intron_variant	Intron 1 of 14			ENSP00000493382.1
PHGDH	ENST00000493622.5	c.-358-3517T>C		intron_variant	Intron 1 of 6	5		ENSP00000493433.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46859 AN: 151766 Hom.: 8221 Cov.: 30

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.304

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.308 AC: 46852 AN: 151884 Hom.: 8218 Cov.: 30 AF XY: 0.305 AC XY: 22635 AN XY: 74210

African (AFR) AF: 0.167 AC: 6918 AN: 41432

American (AMR) AF: 0.311 AC: 4745 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1518 AN: 3466

East Asian (EAS) AF: 0.0559 AC: 289 AN: 5172

South Asian (SAS) AF: 0.297 AC: 1423 AN: 4796

European-Finnish (FIN) AF: 0.376 AC: 3963 AN: 10540

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26907 AN: 67914

Other (OTH) AF: 0.300 AC: 631 AN: 2106

Alfa AF: 0.334 Hom.: 1608

Bravo AF: 0.297

Asia WGS AF: 0.210 AC: 728 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.84
DANN	Benign	0.68
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs541503; hg19: chr1-120208297; COSMIC: COSV72459174;