9-6554680-C-A

Variant names:

• chr9-6554680-C-A
• rs533775952
• NM_000170.3:c.2304G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000170.3(GLDC):​c.2304G>T​(p.Gly768Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G768G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.555
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 9-6554680-C-A is Benign according to our data. Variant chr9-6554680-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1673731.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.555 with no splicing effect.

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.2304G>T	p.Gly768Gly	synonymous	Exon 19 of 25	NP_000161.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.2304G>T	p.Gly768Gly	synonymous	Exon 19 of 25	ENSP00000370737.4
	GLDC	ENST00000638233.1	TSL:1	n.739G>T		non_coding_transcript_exon	Exon 5 of 11
	GLDC	ENST00000639443.1	TSL:1	n.1872G>T		non_coding_transcript_exon	Exon 15 of 21

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457478 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725172

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4370

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109844

Other (OTH) AF: 0.00 AC: 0 AN: 60160

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	7.3
DANN	Benign	0.69
PhyloP100		-0.56
PromoterAI		-0.025	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs533775952; hg19: chr9-6554680;