9-6553514-AT-ATT

Variant names:

• chr9-6553514-A-AT
• rs3215923
• NM_000170.3:c.2316-6dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000170.3(GLDC):​c.2316-6dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,600,546 control chromosomes in the GnomAD database, including 70,396 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5663 hom., cov: 22)
  • Exomes 𝑓: 0.30 (64733 hom.)
• Consequence: GLDC NM_000170.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.07
• Publications: 9 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 -16 ACMG points.

• BP6: Variant 9-6553514-A-AT is Benign according to our data. Variant chr9-6553514-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 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.2316-6dupA		splice_region 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.2316-6dupA		splice_region intron	N/A	ENSP00000370737.4	P23378
	GLDC	ENST00000638233.1	TSL:1	n.751-6dupA		splice_region intron	N/A
	GLDC	ENST00000639443.1	TSL:1	n.1884-6dupA		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39621 AN: 151638 Hom.: 5663 Cov.: 22

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.296 AC: 74154 AN: 250798 AF XY: 0.294

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.303 AC: 438789 AN: 1448790 Hom.: 64733 Cov.: 32 AF XY: 0.304 AC XY: 218972 AN XY: 721230

African (AFR) AF: 0.159 AC: 5318 AN: 33356

American (AMR) AF: 0.356 AC: 15871 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5090 AN: 26042

East Asian (EAS) AF: 0.175 AC: 6946 AN: 39614

South Asian (SAS) AF: 0.316 AC: 27168 AN: 85956

European-Finnish (FIN) AF: 0.316 AC: 16800 AN: 53124

Middle Eastern (MID) AF: 0.232 AC: 1335 AN: 5744

European-Non Finnish (NFE) AF: 0.312 AC: 343873 AN: 1100476

Other (OTH) AF: 0.274 AC: 16388 AN: 59898

GnomAD4 genome AF: 0.261 AC: 39643 AN: 151756 Hom.: 5663 Cov.: 22 AF XY: 0.261 AC XY: 19376 AN XY: 74132

African (AFR) AF: 0.170 AC: 7037 AN: 41412

American (AMR) AF: 0.277 AC: 4227 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3470

East Asian (EAS) AF: 0.187 AC: 967 AN: 5158

South Asian (SAS) AF: 0.319 AC: 1530 AN: 4798

European-Finnish (FIN) AF: 0.307 AC: 3231 AN: 10510

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21228 AN: 67858

Other (OTH) AF: 0.243 AC: 509 AN: 2096

Alfa AF: 0.195 Hom.: 582

Bravo AF: 0.251

EpiCase AF: 0.294

EpiControl AF: 0.287

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Glycine encephalopathy (7)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs3215923; hg19: chr9-6553514; COSMIC: COSV107363224; COSMIC: COSV107363224;