1-119735449-T-G

Variant names:

• chr1-119735449-T-G
• rs146953046
• NM_006623.4:c.792+6T>G

Variant summary

Our verdict is Benign. The variant received -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 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.67
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId is 447938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.792+6T>G		splice_region 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.792+6T>G		splice_region intron	N/A	ENSP00000493175.1	O43175
	PHGDH	ENST00000369409.9	TSL:1	c.792+6T>G		splice_region intron	N/A	ENSP00000358417.5	A0A2C9F2M7
	PHGDH	ENST00000641597.1		c.792+6T>G		splice_region intron	N/A	ENSP00000493382.1	O43175

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

GnomAD2 exomes AF: 0.0111 AC: 2737 AN: 246640 AF XY: 0.0116

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 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

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.00785 AC: 351 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 663 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00567 AC: 489 AN: 86250

European-Finnish (FIN) AF: 0.0108 AC: 551 AN: 50930

Middle Eastern (MID) AF: 0.0225 AC: 129 AN: 5736

European-Non Finnish (NFE) AF: 0.0136 AC: 15092 AN: 1111842

Other (OTH) AF: 0.0130 AC: 786 AN: 60358

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

African (AFR) AF: 0.00226 AC: 94 AN: 41584

American (AMR) AF: 0.0145 AC: 222 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1087 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	PHGDH deficiency (4)
-	-	3	not provided (3)
-	-	1	Neu-Laxova syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		1.7
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs146953046; hg19: chr1-120278072;