chr9-6643754-T-C

Variant names:

• chr9-6643754-T-C
• rs1755615
• NM_000170.3:c.334+860A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000170.3(GLDC):​c.334+860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,414 control chromosomes in the GnomAD database, including 7,963 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7963 hom., cov: 29)
• Consequence: GLDC NM_000170.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0340
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 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.334+860A>G		intron	N/A	NP_000161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.334+860A>G		intron	N/A	ENSP00000370737.4
	GLDC	ENST00000639364.1	TSL:5	n.34+777A>G		intron	N/A
	GLDC	ENST00000639954.1	TSL:5	n.178+860A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47116 AN: 151302 Hom.: 7951 Cov.: 29

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.311 AC: 47152 AN: 151414 Hom.: 7963 Cov.: 29 AF XY: 0.315 AC XY: 23329 AN XY: 73952

African (AFR) AF: 0.385 AC: 15906 AN: 41274

American (AMR) AF: 0.383 AC: 5811 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 999 AN: 3458

East Asian (EAS) AF: 0.575 AC: 2961 AN: 5152

South Asian (SAS) AF: 0.293 AC: 1404 AN: 4786

European-Finnish (FIN) AF: 0.258 AC: 2682 AN: 10404

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16386 AN: 67856

Other (OTH) AF: 0.310 AC: 650 AN: 2098

Alfa AF: 0.258 Hom.: 873

Bravo AF: 0.329

Asia WGS AF: 0.424 AC: 1474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.20
PhyloP100		-0.034
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: rs1755615; hg19: chr9-6643754; COSMIC: COSV58678149; COSMIC: COSV58678149;