6-42963523-C-G

Variant names:

• chr6-42963523-C-G
• rs2296804
• NM_018960.6:c.717-12C>G

Variant summary

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

The NM_018960.6(GNMT):​c.717-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,220 control chromosomes in the GnomAD database, including 290,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (35476 hom., cov: 32)
  • Exomes 𝑓: 0.59 (255426 hom.)
• Consequence: GNMT NM_018960.6 intron
• Scores: Splicing: ADA: 0.001443
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.594
• Publications: 32 publications found

Genes affected

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

GNMT Gene-Disease associations (from GenCC):

• glycine N-methyltransferase deficiency

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-42963523-C-G is Benign according to our data. Variant chr6-42963523-C-G is described in ClinVar as Benign. ClinVar VariationId is 1170128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNMT	NM_018960.6	c.717-12C>G		intron_variant	Intron 5 of 5	ENST00000372808.4	NP_061833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNMT	ENST00000372808.4	c.717-12C>G		intron_variant	Intron 5 of 5	1	NM_018960.6	ENSP00000361894.3

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100664 AN: 151890 Hom.: 35420 Cov.: 32

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.578 AC: 145244 AN: 251348 AF XY: 0.579

Gnomad AFR exome AF: 0.928

Gnomad AMR exome AF: 0.530

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.586 AC: 856835 AN: 1461212 Hom.: 255426 Cov.: 46 AF XY: 0.588 AC XY: 427434 AN XY: 726974

African (AFR) AF: 0.931 AC: 31157 AN: 33472

American (AMR) AF: 0.543 AC: 24283 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13459 AN: 26130

East Asian (EAS) AF: 0.360 AC: 14280 AN: 39700

South Asian (SAS) AF: 0.652 AC: 56192 AN: 86240

European-Finnish (FIN) AF: 0.513 AC: 27387 AN: 53412

Middle Eastern (MID) AF: 0.626 AC: 3612 AN: 5766

European-Non Finnish (NFE) AF: 0.585 AC: 650526 AN: 1111394

Other (OTH) AF: 0.595 AC: 35939 AN: 60376

GnomAD4 genome AF: 0.663 AC: 100783 AN: 152008 Hom.: 35476 Cov.: 32 AF XY: 0.656 AC XY: 48751 AN XY: 74310

African (AFR) AF: 0.917 AC: 38024 AN: 41462

American (AMR) AF: 0.587 AC: 8969 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1769 AN: 3468

East Asian (EAS) AF: 0.335 AC: 1726 AN: 5150

South Asian (SAS) AF: 0.642 AC: 3095 AN: 4822

European-Finnish (FIN) AF: 0.524 AC: 5533 AN: 10566

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39497 AN: 67946

Other (OTH) AF: 0.649 AC: 1370 AN: 2110

Alfa AF: 0.603 Hom.: 5029

Bravo AF: 0.678

Asia WGS AF: 0.544 AC: 1894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.58
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.020		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: rs2296804; hg19: chr6-42931261; COSMIC: COSV55102361; COSMIC: COSV55102361;