9-6553514-AT-ATT

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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.

• BP6: Variant 9-6553514-A-AT is Benign according to our data. Variant chr9-6553514-A-AT is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2316-6dupA		splice_region_variant, intron_variant	Intron 19 of 24	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2316-6_2316-5insA		splice_region_variant, intron_variant	Intron 19 of 24	1	NM_000170.3	ENSP00000370737.4

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

GnomAD3 exomes AF: 0.296 AC: 74154 AN: 250798 Hom.: 11436 AF XY: 0.294 AC XY: 39844 AN XY: 135602

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 SAS exome AF: 0.312

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

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.274

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

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.243

Bravo AF: 0.251

EpiCase AF: 0.294

EpiControl AF: 0.287

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Benign:7

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Sep 27, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLDC c.2316-6dupA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.3 in 121146 control chromosomes in the ExAC database, including 5555 homozygotes. The observed variant frequency is approximately 97-fold above the estimated maximal expected allele frequency for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) phenotype (0.0031), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2316-6dupA in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3215923; hg19: chr9-6553514;