6-42961014-G-C

Variant names:

• chr6-42961014-G-C
• rs5031030
• NM_018960.6:c.206+41G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018960.6(GNMT):​c.206+41G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: GNMT NM_018960.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNMT	NM_018960.6	c.206+41G>C		intron_variant	Intron 1 of 5	ENST00000372808.4	NP_061833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNMT	ENST00000372808.4	c.206+41G>C		intron_variant	Intron 1 of 5	1	NM_018960.6	ENSP00000361894.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333996 Hom.: 0 Cov.: 23 AF XY: 0.00000152 AC XY: 1 AN XY: 657690

African (AFR) AF: 0.00 AC: 0 AN: 30328

American (AMR) AF: 0.00 AC: 0 AN: 34832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24218

East Asian (EAS) AF: 0.00 AC: 0 AN: 35302

South Asian (SAS) AF: 0.00 AC: 0 AN: 77006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4276

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1038186

Other (OTH) AF: 0.00 AC: 0 AN: 55796

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		-2.3
PromoterAI		0.14	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs5031030; hg19: chr6-42928752;