rs35374927

Variant names:

• chr9-6610326-C-T
• rs35374927
• NM_000170.3:c.501G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.501G>A​(p.Glu167Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,612,998 control chromosomes in the GnomAD database, including 59,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4243 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55165 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.417
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 9-6610326-C-T is Benign according to our data. Variant chr9-6610326-C-T is described in ClinVar as Benign. ClinVar VariationId is 255459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.417 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

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.501G>A	p.Glu167Glu	synonymous	Exon 4 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.501G>A	p.Glu167Glu	synonymous	Exon 4 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000920236.1		c.501G>A	p.Glu167Glu	synonymous	Exon 4 of 25	ENSP00000590295.1
	GLDC	ENST00000953081.1		c.501G>A	p.Glu167Glu	synonymous	Exon 4 of 26	ENSP00000623139.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34405 AN: 152020 Hom.: 4241 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.238 AC: 59621 AN: 250824 AF XY: 0.245

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.0887

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.271 AC: 395632 AN: 1460858 Hom.: 55165 Cov.: 33 AF XY: 0.272 AC XY: 197641 AN XY: 726746

African (AFR) AF: 0.143 AC: 4791 AN: 33476

American (AMR) AF: 0.176 AC: 7876 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5919 AN: 26130

East Asian (EAS) AF: 0.0829 AC: 3290 AN: 39700

South Asian (SAS) AF: 0.274 AC: 23590 AN: 86190

European-Finnish (FIN) AF: 0.265 AC: 14149 AN: 53408

Middle Eastern (MID) AF: 0.292 AC: 1683 AN: 5768

European-Non Finnish (NFE) AF: 0.287 AC: 319121 AN: 1111116

Other (OTH) AF: 0.252 AC: 15213 AN: 60374

GnomAD4 genome AF: 0.226 AC: 34418 AN: 152140 Hom.: 4243 Cov.: 32 AF XY: 0.226 AC XY: 16781 AN XY: 74380

African (AFR) AF: 0.144 AC: 5991 AN: 41544

American (AMR) AF: 0.219 AC: 3341 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 768 AN: 3470

East Asian (EAS) AF: 0.0921 AC: 477 AN: 5180

South Asian (SAS) AF: 0.270 AC: 1305 AN: 4826

European-Finnish (FIN) AF: 0.261 AC: 2759 AN: 10574

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.281 AC: 19092 AN: 67948

Other (OTH) AF: 0.247 AC: 521 AN: 2110

Alfa AF: 0.253 Hom.: 2368

Bravo AF: 0.216

Asia WGS AF: 0.186 AC: 647 AN: 3478

EpiCase AF: 0.287

EpiControl AF: 0.284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycine encephalopathy (5)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.7
DANN	Benign	0.46
PhyloP100		0.42
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: rs35374927; hg19: chr9-6610326; COSMIC: COSV58680519; COSMIC: COSV58680519;