rs41281773

Positions:

• chr9-6558693-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000321612.8(GLDC):​c.1927-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,996 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: GLDC ENST00000321612.8 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007716
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0250

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-6558693-T-C is Benign according to our data. Variant chr9-6558693-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 367184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6558693-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.1927-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.1927-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000170.3	ENSP00000370737	P1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00175 AC: 440 AN: 251426 Hom.: 2 AF XY: 0.00183 AC XY: 248 AN XY: 135872

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00304 AC: 4440 AN: 1461816 Hom.: 8 Cov.: 31 AF XY: 0.00294 AC XY: 2141 AN XY: 727214

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74396

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00179

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 31, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Non-ketotic hyperglycinemia Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000077
dbscSNV1_RF	Benign	0.012
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

Publications

LitVar

Other links and lift over

dbSNP: rs41281773; hg19: chr9-6558693;