rs142004524

Variant names:

• chr9-6533125-C-T
• rs142004524
• NM_000170.3:c.2955G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-6533125-C-T
• chr9-6533125-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_000170.3(GLDC):​c.2955G>A​(p.Thr985Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,612,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.765
• Publications: 0 publications found

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

GLDC Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
• glycine encephalopathy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-6533125-C-T is Benign according to our data. Variant chr9-6533125-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 462882.
• BP7: Synonymous conserved (PhyloP=0.765 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (180/152186) while in subpopulation AFR AF = 0.00412 (171/41516). AF 95% confidence interval is 0.00361. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. 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
	GLDC	NM_000170.3	MANE Select	c.2955G>A	p.Thr985Thr	synonymous	Exon 25 of 25	NP_000161.2	P23378

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.2955G>A	p.Thr985Thr	synonymous	Exon 25 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000638233.1	TSL:1	n.1390G>A		non_coding_transcript_exon	Exon 11 of 11
	GLDC	ENST00000639443.1	TSL:1	n.2523G>A		non_coding_transcript_exon	Exon 21 of 21

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251428 AF XY: 0.000169

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1460708 Hom.: 1 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 726768

African (AFR) AF: 0.00424 AC: 142 AN: 33456

American (AMR) AF: 0.000268 AC: 12 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110938

Other (OTH) AF: 0.000480 AC: 29 AN: 60364

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74388

African (AFR) AF: 0.00412 AC: 171 AN: 41516

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000425 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Glycine encephalopathy (2)
-	-	2	not provided (2)
-	-	1	GLDC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.39
PhyloP100		0.77

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: rs142004524; hg19: chr9-6533125; COSMIC: COSV58679518;