rs2296805

Variant names:

• chr6-42961020-T-G
• rs2296805
• NM_018960.6:c.206+47T>G

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+47T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,456,542 control chromosomes in the GnomAD database, including 264,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.66 (35321 hom., cov: 33)
  • Exomes 𝑓: 0.59 (229499 hom.)
• Consequence: GNMT NM_018960.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.96
• Publications: 25 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 6-42961020-T-G is Benign according to our data. Variant chr6-42961020-T-G is described in ClinVar as Benign. ClinVar VariationId is 1265698.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNMT	NM_018960.6	c.206+47T>G		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+47T>G		intron_variant	Intron 1 of 5	1	NM_018960.6	ENSP00000361894.3

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100590 AN: 152078 Hom.: 35265 Cov.: 33

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.646

GnomAD2 exomes AF: 0.574 AC: 67666 AN: 117892 AF XY: 0.578

Gnomad AFR exome AF: 0.924

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.343

Gnomad FIN exome AF: 0.512

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.589 AC: 767795 AN: 1304346 Hom.: 229499 Cov.: 21 AF XY: 0.590 AC XY: 379411 AN XY: 642802

African (AFR) AF: 0.925 AC: 27473 AN: 29710

American (AMR) AF: 0.550 AC: 18773 AN: 34106

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 12164 AN: 23600

East Asian (EAS) AF: 0.360 AC: 12539 AN: 34828

South Asian (SAS) AF: 0.652 AC: 49202 AN: 75514

European-Finnish (FIN) AF: 0.507 AC: 16957 AN: 33430

Middle Eastern (MID) AF: 0.632 AC: 2590 AN: 4100

European-Non Finnish (NFE) AF: 0.587 AC: 595410 AN: 1014282

Other (OTH) AF: 0.597 AC: 32687 AN: 54776

GnomAD4 genome AF: 0.662 AC: 100709 AN: 152196 Hom.: 35321 Cov.: 33 AF XY: 0.655 AC XY: 48733 AN XY: 74420

African (AFR) AF: 0.911 AC: 37877 AN: 41560

American (AMR) AF: 0.586 AC: 8967 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1773 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1737 AN: 5164

South Asian (SAS) AF: 0.642 AC: 3100 AN: 4828

European-Finnish (FIN) AF: 0.523 AC: 5548 AN: 10600

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.582 AC: 39539 AN: 67968

Other (OTH) AF: 0.648 AC: 1372 AN: 2116

Alfa AF: 0.597 Hom.: 8011

Bravo AF: 0.677

Asia WGS AF: 0.544 AC: 1895 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.56
PhyloP100		2.0
PromoterAI		0.047	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: rs2296805; hg19: chr6-42928758;