NM_006623.4:c.138+343A>G

Variant names:

• chr1-119712503-A-G
• rs478093
• NM_006623.4:c.138+343A>G

Variant summary

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

The NM_006623.4(PHGDH):​c.138+343A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 350,550 control chromosomes in the GnomAD database, including 92,835 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 0.73 (41463 hom., cov: 35)
  • Exomes 𝑓: 0.72 (51372 hom.)
• Consequence: PHGDH NM_006623.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 24 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

ENSG00000296692 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

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.138+343A>G		intron	N/A	NP_006614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	ENST00000641023.2	MANE Select	c.138+343A>G		intron	N/A	ENSP00000493175.1	O43175
	PHGDH	ENST00000369409.9	TSL:1	c.138+343A>G		intron	N/A	ENSP00000358417.5	A0A2C9F2M7
	PHGDH	ENST00000641597.1		c.138+343A>G		intron	N/A	ENSP00000493382.1	O43175

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111792 AN: 152122 Hom.: 41423 Cov.: 35

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.742

GnomAD4 exome AF: 0.715 AC: 141856 AN: 198312 Hom.: 51372 Cov.: 0 AF XY: 0.720 AC XY: 77329 AN XY: 107464

African (AFR) AF: 0.791 AC: 4341 AN: 5486

American (AMR) AF: 0.711 AC: 6765 AN: 9512

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 3283 AN: 4938

East Asian (EAS) AF: 0.945 AC: 8195 AN: 8676

South Asian (SAS) AF: 0.752 AC: 28161 AN: 37452

European-Finnish (FIN) AF: 0.664 AC: 5747 AN: 8650

Middle Eastern (MID) AF: 0.688 AC: 490 AN: 712

European-Non Finnish (NFE) AF: 0.691 AC: 78029 AN: 113000

Other (OTH) AF: 0.692 AC: 6845 AN: 9886

GnomAD4 genome AF: 0.735 AC: 111888 AN: 152238 Hom.: 41463 Cov.: 35 AF XY: 0.737 AC XY: 54837 AN XY: 74418

African (AFR) AF: 0.801 AC: 33269 AN: 41558

American (AMR) AF: 0.732 AC: 11194 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2304 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4875 AN: 5164

South Asian (SAS) AF: 0.765 AC: 3697 AN: 4830

European-Finnish (FIN) AF: 0.673 AC: 7140 AN: 10604

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 47011 AN: 67994

Other (OTH) AF: 0.745 AC: 1574 AN: 2112

Alfa AF: 0.709 Hom.: 51897

Bravo AF: 0.740

Asia WGS AF: 0.809 AC: 2806 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	12
DANN	Benign	0.42
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs478093; hg19: chr1-120255126;