ENST00000641597:c.-101G>C

Variant names:

• chr1-119711922-G-C
• rs562038
• ENST00000641597:c.-101G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000641597(PHGDH):​c.-101G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 1,213,964 control chromosomes in the GnomAD database, including 317,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44369 hom., cov: 32)
  • Exomes 𝑓: 0.71 (272988 hom.)
• Consequence: PHGDH ENST00000641597 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.563

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]

LOC105378937 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-119711922-G-C is Benign according to our data. Variant chr1-119711922-G-C is described in ClinVar as [Benign]. Clinvar id is 292300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119711922-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.-101G>C		upstream_gene_variant		ENST00000641023.2	NP_006614.2
PHGDH	XM_011541226.3	c.-101G>C		upstream_gene_variant			XP_011539528.1
PHGDH	XR_007058634.1	n.-12G>C		upstream_gene_variant
LOC105378937	XR_947757.4	n.-76C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.-101G>C		upstream_gene_variant			NM_006623.4	ENSP00000493175.1

Frequencies

GnomAD3 genomes AF: 0.757 AC: 115181 AN: 152056 Hom.: 44316 Cov.: 32

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.756

GnomAD4 exome AF: 0.715 AC: 759073 AN: 1061790 Hom.: 272988 Cov.: 14 AF XY: 0.715 AC XY: 390416 AN XY: 546254

Gnomad4 AFR exome AF: 0.897

Gnomad4 AMR exome AF: 0.707

Gnomad4 ASJ exome AF: 0.664

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.718

GnomAD4 genome AF: 0.758 AC: 115293 AN: 152174 Hom.: 44369 Cov.: 32 AF XY: 0.759 AC XY: 56431 AN XY: 74376

Gnomad4 AFR AF: 0.885

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.943

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.673

Gnomad4 NFE AF: 0.688

Gnomad4 OTH AF: 0.760

Alfa AF: 0.624 Hom.: 1752

Bravo AF: 0.767

Asia WGS AF: 0.821 AC: 2856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:2

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neu-Laxova syndrome 1 Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.96
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs562038; hg19: chr1-120254545; COSMIC: COSV65582685; COSMIC: COSV65582685;