Genetic Variant NM_006623.4:c.13A>C (chr1-119712035-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006623.4(PHGDH):c.13A>C(p.Asn5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N5D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.744

Publications

0 publications found

Variant links:

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

PHGDH links:

ENSG00000296692 (HGNC:):

ENSG00000296692 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30623513).

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.13A>C	p.Asn5His	missense	Exon 1 of 12	NP_006614.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHGDH	ENST00000641023.2	MANE Select	c.13A>C	p.Asn5His	missense	Exon 1 of 12	ENSP00000493175.1	O43175
PHGDH	ENST00000369409.9	TSL:1	c.13A>C	p.Asn5His	missense	Exon 1 of 12	ENSP00000358417.5	A0A2C9F2M7
PHGDH	ENST00000641597.1		c.13A>C	p.Asn5His	missense	Exon 4 of 15	ENSP00000493382.1	O43175

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.033

MutationAssessor

Benign

1.7

PhyloP100

0.74

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.32

Sift

Uncertain

0.011

Sift4G

Benign

0.092

Polyphen

0.97

Vest4

0.11

MutPred

0.47

Gain of ubiquitination at F8 (P = 0.0745)

MVP

0.95

MPC

0.36

ClinPred

0.85

GERP RS

4.0

PromoterAI

-0.078

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.29

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over