rs144666843

Variant names:

• chr9-6588393-C-T
• rs144666843
• NM_000170.3:c.1707+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-6588393-C-T
• chr9-6588393-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000170.3(GLDC):​c.1707+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,603,864 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (48 hom.)
• Consequence: GLDC NM_000170.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005711
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.54
• Publications: 4 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=-0.82).
• BP6: Variant 9-6588393-C-T is Benign according to our data. Variant chr9-6588393-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00451 (686/152220) while in subpopulation NFE AF = 0.00749 (509/68002). AF 95% confidence interval is 0.00695. There are 4 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown gene

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.1707+8G>A		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.1707+8G>A		splice_region intron	N/A	ENSP00000370737.4	P23378
	GLDC	ENST00000639443.1	TSL:1	n.1275+8G>A		splice_region intron	N/A
	GLDC	ENST00000920236.1		c.1707+8G>A		splice_region intron	N/A	ENSP00000590295.1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152102 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00490 AC: 1231 AN: 251456 AF XY: 0.00482

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.00694

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00634 AC: 9200 AN: 1451644 Hom.: 48 Cov.: 29 AF XY: 0.00620 AC XY: 4484 AN XY: 722964

African (AFR) AF: 0.000812 AC: 27 AN: 33254

American (AMR) AF: 0.00259 AC: 116 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 113 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00315 AC: 271 AN: 86058

European-Finnish (FIN) AF: 0.00745 AC: 398 AN: 53408

Middle Eastern (MID) AF: 0.00487 AC: 28 AN: 5744

European-Non Finnish (NFE) AF: 0.00719 AC: 7930 AN: 1102732

Other (OTH) AF: 0.00528 AC: 317 AN: 60010

GnomAD4 genome AF: 0.00451 AC: 686 AN: 152220 Hom.: 4 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74418

African (AFR) AF: 0.000818 AC: 34 AN: 41550

American (AMR) AF: 0.00222 AC: 34 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.00632 AC: 67 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00749 AC: 509 AN: 68002

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00552 Hom.: 1

Bravo AF: 0.00407

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00610

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycine encephalopathy (3)
-	-	2	not provided (2)
-	-	1	GLDC-related disorder (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.22
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs144666843; hg19: chr9-6588393;