6-42961014-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018960.6(GNMT):​c.206+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,486,288 control chromosomes in the GnomAD database, including 817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (465 hom., cov: 34)
  • Exomes 𝑓: 0.0042 (352 hom.)
• Consequence: GNMT NM_018960.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-42961014-G-A is Benign according to our data. Variant chr6-42961014-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018960.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	NM_018960.6	MANE Select	c.206+41G>A		intron	N/A	NP_061833.1
	GNMT	NM_001318865.2		c.206+41G>A		intron	N/A	NP_001305794.1
	CNPY3-GNMT	NM_001318857.2		c.152-1748G>A		intron	N/A	NP_001305786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.206+41G>A		intron	N/A	ENSP00000361894.3

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6311 AN: 152214 Hom.: 465 Cov.: 34

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.00906 AC: 1102 AN: 121666 AF XY: 0.00718

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000445

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00424 AC: 5653 AN: 1333956 Hom.: 352 Cov.: 23 AF XY: 0.00358 AC XY: 2355 AN XY: 657672

African (AFR) AF: 0.151 AC: 4578 AN: 30298

American (AMR) AF: 0.00867 AC: 302 AN: 34830

Ashkenazi Jewish (ASJ) AF: 0.000124 AC: 3 AN: 24218

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

South Asian (SAS) AF: 0.000312 AC: 24 AN: 77006

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

Middle Eastern (MID) AF: 0.00608 AC: 26 AN: 4276

European-Non Finnish (NFE) AF: 0.000223 AC: 232 AN: 1038186

Other (OTH) AF: 0.00875 AC: 488 AN: 55788

GnomAD4 genome AF: 0.0415 AC: 6319 AN: 152332 Hom.: 465 Cov.: 34 AF XY: 0.0405 AC XY: 3014 AN XY: 74500

African (AFR) AF: 0.144 AC: 5964 AN: 41560

American (AMR) AF: 0.0157 AC: 240 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68034

Other (OTH) AF: 0.0341 AC: 72 AN: 2114

Alfa AF: 0.00926 Hom.: 9

Bravo AF: 0.0483

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.79
PhyloP100		-2.3
PromoterAI		0.11	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;