chr9-6606639-A-G

Variant names:

• chr9-6606639-A-G
• rs12004164
• NM_000170.3:c.666T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.666T>C​(p.Asp222Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,608,470 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (133 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.874
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-6606639-A-G is Benign according to our data. Variant chr9-6606639-A-G is described in ClinVar as Benign. ClinVar VariationId is 367201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.874 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0776 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.666T>C	p.Asp222Asp	synonymous	Exon 5 of 25	NP_000161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.666T>C	p.Asp222Asp	synonymous	Exon 5 of 25	ENSP00000370737.4
	GLDC	ENST00000920236.1		c.666T>C	p.Asp222Asp	synonymous	Exon 5 of 25	ENSP00000590295.1
	GLDC	ENST00000953081.1		c.666T>C	p.Asp222Asp	synonymous	Exon 5 of 26	ENSP00000623139.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3688 AN: 152166 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00946 AC: 2380 AN: 251462 AF XY: 0.00900

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00360 AC: 5238 AN: 1456186 Hom.: 133 Cov.: 28 AF XY: 0.00384 AC XY: 2780 AN XY: 724890

African (AFR) AF: 0.0730 AC: 2393 AN: 32794

American (AMR) AF: 0.00552 AC: 247 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.000933 AC: 37 AN: 39674

South Asian (SAS) AF: 0.0191 AC: 1645 AN: 86072

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

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5758

European-Non Finnish (NFE) AF: 0.000383 AC: 424 AN: 1107476

Other (OTH) AF: 0.00771 AC: 464 AN: 60178

GnomAD4 genome AF: 0.0244 AC: 3715 AN: 152284 Hom.: 141 Cov.: 32 AF XY: 0.0244 AC XY: 1818 AN XY: 74478

African (AFR) AF: 0.0799 AC: 3319 AN: 41550

American (AMR) AF: 0.0129 AC: 197 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5190

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68018

Other (OTH) AF: 0.0203 AC: 43 AN: 2116

Alfa AF: 0.0113 Hom.: 33

Bravo AF: 0.0273

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycine encephalopathy (3)
-	-	2	not provided (2)
-	-	1	GLDC-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.2
DANN	Benign	0.51
PhyloP100		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12004164; hg19: chr9-6606639;