1-119735449-T-G

Position:

• chr1-119735449-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_006623.4(PHGDH):​c.792+6T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,611,482 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (128 hom.)
• Consequence: PHGDH NM_006623.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 1-119735449-T-G is Benign according to our data. Variant chr1-119735449-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 447938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119735449-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1685/152340) while in subpopulation NFE AF= 0.016 (1087/68024). AF 95% confidence interval is 0.0152. There are 10 homozygotes in gnomad4. There are 781 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHGDH	NM_006623.4	c.792+6T>G		splice_donor_region_variant, intron_variant		ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2	c.792+6T>G		splice_donor_region_variant, intron_variant			NM_006623.4	ENSP00000493175	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152222 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0111 AC: 2737 AN: 246640 Hom.: 18 AF XY: 0.0116 AC XY: 1557 AN XY: 133748

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00797

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00575

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0124 AC: 18124 AN: 1459142 Hom.: 128 Cov.: 32 AF XY: 0.0125 AC XY: 9051 AN XY: 725990

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00567

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0111 AC: 1685 AN: 152340 Hom.: 10 Cov.: 33 AF XY: 0.0105 AC XY: 781 AN XY: 74504

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0158 Hom.: 6

Bravo AF: 0.0102

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0157

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:4

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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PHGDH: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 33087887) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neu-Laxova syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.020		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: rs146953046; hg19: chr1-120278072;