rs4987173

Variant names:

• chr6-42963486-G-A
• rs4987173
• NM_018960.6:c.716+37G>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.716+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,613,324 control chromosomes in the GnomAD database, including 152,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13022 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139946 hom.)
• Consequence: GNMT NM_018960.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.491
• Publications: 27 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=-0.84).
• BP6: Variant 6-42963486-G-A is Benign according to our data. Variant chr6-42963486-G-A is described in ClinVar as Benign. ClinVar VariationId is 1251337.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNMT	NM_018960.6	c.716+37G>A		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.716+37G>A		intron_variant	Intron 5 of 5	1	NM_018960.6	ENSP00000361894.3

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62049 AN: 151830 Hom.: 13017 Cov.: 31

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.386 AC: 96861 AN: 251258 AF XY: 0.396

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.432 AC: 631602 AN: 1461380 Hom.: 139946 Cov.: 45 AF XY: 0.434 AC XY: 315404 AN XY: 727032

African (AFR) AF: 0.401 AC: 13421 AN: 33460

American (AMR) AF: 0.274 AC: 12239 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10785 AN: 26132

East Asian (EAS) AF: 0.125 AC: 4955 AN: 39700

South Asian (SAS) AF: 0.433 AC: 37308 AN: 86246

European-Finnish (FIN) AF: 0.394 AC: 21055 AN: 53414

Middle Eastern (MID) AF: 0.463 AC: 2669 AN: 5768

European-Non Finnish (NFE) AF: 0.453 AC: 503915 AN: 1111566

Other (OTH) AF: 0.418 AC: 25255 AN: 60384

GnomAD4 genome AF: 0.409 AC: 62090 AN: 151944 Hom.: 13022 Cov.: 31 AF XY: 0.404 AC XY: 30014 AN XY: 74270

African (AFR) AF: 0.395 AC: 16337 AN: 41390

American (AMR) AF: 0.341 AC: 5213 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3470

East Asian (EAS) AF: 0.105 AC: 541 AN: 5174

South Asian (SAS) AF: 0.404 AC: 1946 AN: 4818

European-Finnish (FIN) AF: 0.405 AC: 4284 AN: 10568

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30821 AN: 67942

Other (OTH) AF: 0.418 AC: 883 AN: 2110

Alfa AF: 0.433 Hom.: 3179

Bravo AF: 0.401

Asia WGS AF: 0.258 AC: 899 AN: 3476

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.57
DANN	Benign	0.56
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs4987173; hg19: chr6-42931224; COSMIC: COSV55102220; COSMIC: COSV55102220;