chr1-119711883-A-G

Variant names:

• chr1-119711883-A-G
• rs561931
• ENST00000641597.1:c.-140A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Neu-Laxova syndrome 1

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• Neu-Laxova syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296692 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 292299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000641597.1. 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.-140A>G		upstream_gene	N/A	NP_006614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	ENST00000641597.1		c.-140A>G		5_prime_UTR	Exon 4 of 15	ENSP00000493382.1	O43175
	PHGDH	ENST00000641720.1		c.-140A>G		5_prime_UTR	Exon 2 of 3	ENSP00000492948.1	A0A286YF34
	PHGDH	ENST00000493622.5	TSL:5	c.-147-9287A>G		intron	N/A	ENSP00000493433.1	A0A286YFE1

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

African (AFR) AF: 0.603 AC: 10953 AN: 18150

American (AMR) AF: 0.652 AC: 24382 AN: 37402

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 12391 AN: 20066

East Asian (EAS) AF: 0.929 AC: 32052 AN: 34520

South Asian (SAS) AF: 0.728 AC: 48005 AN: 65900

European-Finnish (FIN) AF: 0.614 AC: 29574 AN: 48162

Middle Eastern (MID) AF: 0.644 AC: 1701 AN: 2642

European-Non Finnish (NFE) AF: 0.598 AC: 237324 AN: 397064

Other (OTH) AF: 0.625 AC: 20933 AN: 33514

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

African (AFR) AF: 0.600 AC: 24882 AN: 41480

American (AMR) AF: 0.661 AC: 10084 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2160 AN: 3466

East Asian (EAS) AF: 0.942 AC: 4870 AN: 5170

South Asian (SAS) AF: 0.746 AC: 3597 AN: 4824

European-Finnish (FIN) AF: 0.621 AC: 6552 AN: 10544

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40356 AN: 67958

Other (OTH) AF: 0.652 AC: 1374 AN: 2106

Alfa AF: 0.613 Hom.: 3614

Bravo AF: 0.623

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.52
PhyloP100		0.68
PromoterAI		0.0044	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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