rs73400312

Variant names:

• chr9-6592868-G-C
• rs73400312
• NM_000170.3:c.1384C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-6592868-G-C
• chr9-6592868-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000170.3(GLDC):​c.1384C>G​(p.Leu462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,522 control chromosomes in the GnomAD database, including 900 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L462L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (420 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (480 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.477
• Publications: 8 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000170.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021384656).
• BP6: Variant 9-6592868-G-C is Benign according to our data. Variant chr9-6592868-G-C is described in ClinVar as Benign. ClinVar VariationId is 367193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 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.1384C>G	p.Leu462Val	missense	Exon 10 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.1384C>G	p.Leu462Val	missense	Exon 10 of 25	ENSP00000370737.4
	GLDC	ENST00000639443.1	TSL:1	n.952C>G		non_coding_transcript_exon	Exon 6 of 21
	GLDC	ENST00000463305.1	TSL:3	n.*158C>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000491209.1

Frequencies

GnomAD3 genomes AF: 0.0445 AC: 6773 AN: 152184 Hom.: 418 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0187 AC: 4701 AN: 251430 AF XY: 0.0174

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.00960 AC: 14029 AN: 1461220 Hom.: 480 Cov.: 31 AF XY: 0.00980 AC XY: 7122 AN XY: 726944

African (AFR) AF: 0.143 AC: 4784 AN: 33448

American (AMR) AF: 0.0124 AC: 554 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 611 AN: 26136

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39700

South Asian (SAS) AF: 0.0329 AC: 2838 AN: 86220

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53420

Middle Eastern (MID) AF: 0.0165 AC: 88 AN: 5336

European-Non Finnish (NFE) AF: 0.00356 AC: 3960 AN: 1111910

Other (OTH) AF: 0.0179 AC: 1080 AN: 60330

GnomAD4 genome AF: 0.0446 AC: 6796 AN: 152302 Hom.: 420 Cov.: 32 AF XY: 0.0430 AC XY: 3203 AN XY: 74476

African (AFR) AF: 0.136 AC: 5643 AN: 41546

American (AMR) AF: 0.0312 AC: 477 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.00424 AC: 22 AN: 5188

South Asian (SAS) AF: 0.0371 AC: 179 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68030

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.00641 Hom.: 5

Bravo AF: 0.0509

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.135 AC: 593

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.0215 AC: 2611

Asia WGS AF: 0.0670 AC: 234 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00539

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.36	N
PhyloP100		0.48
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.17
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.046
ClinPred		0.00043	T
GERP RS		2.6
Varity_R		0.16
gMVP		0.45
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs73400312; hg19: chr9-6592868;