rs11789777

Variant names:

• chr9-6594978-T-C
• rs11789777
• NM_000170.3:c.1261+36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000170.3(GLDC):​c.1261+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,226,890 control chromosomes in the GnomAD database, including 40,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3903 hom., cov: 33)
  • Exomes 𝑓: 0.26 (36956 hom.)
• Consequence: GLDC NM_000170.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.839
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-6594978-T-C is Benign according to our data. Variant chr9-6594978-T-C is described in ClinVar as Benign. ClinVar VariationId is 1185251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.281 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.1261+36A>G		intron	N/A	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.1261+36A>G		intron	N/A	ENSP00000370737.4	P23378
	GLDC	ENST00000639443.1	TSL:1	n.829+36A>G		intron	N/A
	GLDC	ENST00000920236.1		c.1261+36A>G		intron	N/A	ENSP00000590295.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32259 AN: 152080 Hom.: 3906 Cov.: 33

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.238

GnomAD2 exomes AF: 0.251 AC: 62950 AN: 250624 AF XY: 0.253

Gnomad AFR exome AF: 0.0903

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.258 AC: 277508 AN: 1074692 Hom.: 36956 Cov.: 16 AF XY: 0.260 AC XY: 143351 AN XY: 552068

African (AFR) AF: 0.0916 AC: 2393 AN: 26122

American (AMR) AF: 0.315 AC: 13947 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5297 AN: 23748

East Asian (EAS) AF: 0.154 AC: 5853 AN: 38020

South Asian (SAS) AF: 0.277 AC: 21748 AN: 78460

European-Finnish (FIN) AF: 0.252 AC: 13377 AN: 52992

Middle Eastern (MID) AF: 0.263 AC: 1171 AN: 4446

European-Non Finnish (NFE) AF: 0.266 AC: 202241 AN: 759112

Other (OTH) AF: 0.242 AC: 11481 AN: 47528

GnomAD4 genome AF: 0.212 AC: 32255 AN: 152198 Hom.: 3903 Cov.: 33 AF XY: 0.213 AC XY: 15885 AN XY: 74410

African (AFR) AF: 0.0924 AC: 3839 AN: 41546

American (AMR) AF: 0.288 AC: 4408 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3468

East Asian (EAS) AF: 0.167 AC: 864 AN: 5184

South Asian (SAS) AF: 0.279 AC: 1343 AN: 4822

European-Finnish (FIN) AF: 0.251 AC: 2651 AN: 10582

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17743 AN: 67992

Other (OTH) AF: 0.239 AC: 506 AN: 2114

Alfa AF: 0.248 Hom.: 15744

Bravo AF: 0.208

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.78
PhyloP100		0.84
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: rs11789777; hg19: chr9-6594978; COSMIC: COSV58680914; COSMIC: COSV58680914;