1-119711883-A-G

Position:

• chr1-119711883-A-G

Variant summary

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

The ENST00000641597.1(PHGDH):​c.-140A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 809,436 control chromosomes in the GnomAD database, including 163,879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29845 hom., cov: 32)
  • Exomes 𝑓: 0.63 (134034 hom.)
• Consequence: PHGDH ENST00000641597.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.683

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=-0.83).
• BP6: Variant 1-119711883-A-G is Benign according to our data. Variant chr1-119711883-A-G is described in ClinVar as [Benign]. Clinvar id is 292299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119711883-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC105378937	XR_947757.4			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHGDH	ENST00000641597.1	c.-140A>G		5_prime_UTR_variant	4/15			P1
PHGDH	ENST00000641720.1	c.-140A>G		5_prime_UTR_variant	2/3
PHGDH	ENST00000493622.5	c.-147-9287A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94549 AN: 151898 Hom.: 29822 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.648

GnomAD4 exome AF: 0.635 AC: 417315 AN: 657420 Hom.: 134034 Cov.: 8 AF XY: 0.640 AC XY: 225315 AN XY: 351900

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.652

Gnomad4 ASJ exome AF: 0.618

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.614

Gnomad4 NFE exome AF: 0.598

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.622 AC: 94623 AN: 152016 Hom.: 29845 Cov.: 32 AF XY: 0.628 AC XY: 46688 AN XY: 74296

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.623

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.746

Gnomad4 FIN AF: 0.621

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.652

Alfa AF: 0.613 Hom.: 3614

Bravo AF: 0.623

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	- -

Neu-Laxova syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs561931; hg19: chr1-120254506; COSMIC: COSV65582678; COSMIC: COSV65582678;