3-49417897-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000481.4(AMT):c.954G>A(p.Arg318Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,613,826 control chromosomes in the GnomAD database, including 75,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6559 hom., cov: 31)

Exomes 𝑓: 0.30 ( 68709 hom. )

Consequence

AMT
NM_000481.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.891

Publications

80 publications found

Variant links:

Genes affected

AMT (HGNC:473): (aminomethyltransferase) This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

AMT Gene-Disease associations (from GenCC):

glycine encephalopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
glycine encephalopathy 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
infantile glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
neonatal glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atypical glycine encephalopathy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

AMT links:

ENSG00000283189 (HGNC:):

ENSG00000283189 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.047).

BP6

Variant 3-49417897-C-T is Benign according to our data. Variant chr3-49417897-C-T is described in ClinVar as Benign. ClinVar VariationId is 256240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.891 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4 link	c.954G>A	p.Arg318Arg	synonymous_variant	Exon 8 of 9	ENST00000273588.9	NP_000472.2	P48728-1A0A024R2U7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9 link	c.954G>A	p.Arg318Arg	synonymous_variant	Exon 8 of 9	1	NM_000481.4	ENSP00000273588.3		P48728-1
ENSG00000283189	ENST00000636166.1 link	c.1191G>A	p.Arg397Arg	synonymous_variant	Exon 10 of 11	5		ENSP00000490106.1		A0A1B0GUH1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42689

AN:

151924

Hom.:

6557

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.0584

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.288

GnomAD2 exomes

AF:

0.276

AC:

69306

AN:

251004

AF XY:

0.280

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.154

Gnomad ASJ exome

AF:

0.456

Gnomad EAS exome

AF:

0.0558

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.298

AC:

435990

AN:

1461786

Hom.:

68709

Cov.:

AF XY:

0.297

AC XY:

216045

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.235

AC:

7864

AN:

33480

American (AMR)

AF:

0.161

AC:

7199

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

11886

AN:

26136

East Asian (EAS)

AF:

0.0630

AC:

2502

AN:

39700

South Asian (SAS)

AF:

0.243

AC:

20957

AN:

86258

European-Finnish (FIN)

AF:

0.454

AC:

24219

AN:

53342

Middle Eastern (MID)

AF:

0.316

AC:

1820

AN:

5768

European-Non Finnish (NFE)

AF:

0.307

AC:

341434

AN:

1111996

Other (OTH)

AF:

0.300

AC:

18109

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

20224

40447

60671

80894

101118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10998

21996

32994

43992

54990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.281

AC:

42703

AN:

152040

Hom.:

6559

Cov.:

AF XY:

0.284

AC XY:

21086

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.235

AC:

9732

AN:

41480

American (AMR)

AF:

0.216

AC:

3303

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1601

AN:

3472

East Asian (EAS)

AF:

0.0587

AC:

303

AN:

5160

South Asian (SAS)

AF:

0.226

AC:

1090

AN:

4824

European-Finnish (FIN)

AF:

0.472

AC:

4972

AN:

10536

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20824

AN:

67966

Other (OTH)

AF:

0.286

AC:

604

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1509

3017

4526

6034

7543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.293

Hom.:

21421

Bravo

AF:

0.258

Asia WGS

AF:

0.143

AC:

503

AN:

3478

EpiCase

AF:

0.317

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:6

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 14, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 26, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28502726, 12948742, 22171071) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over