dbSNP rs116192290: AMT:p.Glu211Lys (chr3-49419325-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000481.4(AMT):c.631G>A(p.Glu211Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,614,230 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E211E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0079 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 109 hom. )

Consequence

AMT
NM_000481.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.57

Publications

17 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, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008803636).

BP6

Variant 3-49419325-C-T is Benign according to our data. Variant chr3-49419325-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00791 (1205/152350) while in subpopulation SAS AF = 0.0174 (84/4832). AF 95% confidence interval is 0.0144. There are 5 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMT	NM_000481.4	MANE Select	c.631G>A	p.Glu211Lys	missense	Exon 6 of 9	NP_000472.2
AMT	NM_001164712.2		c.631G>A	p.Glu211Lys	missense	Exon 6 of 10	NP_001158184.1	P48728-4
AMT	NM_001164710.2		c.499G>A	p.Glu167Lys	missense	Exon 5 of 8	NP_001158182.1	P48728-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMT	ENST00000273588.9	TSL:1 MANE Select	c.631G>A	p.Glu211Lys	missense	Exon 6 of 9	ENSP00000273588.3	P48728-1
ENSG00000283189	ENST00000636166.1	TSL:5	c.868G>A	p.Glu290Lys	missense	Exon 8 of 11	ENSP00000490106.1	A0A1B0GUH1
AMT	ENST00000395338.7	TSL:1	c.631G>A	p.Glu211Lys	missense	Exon 6 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes

AF:

0.00790

AC:

1202

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00994

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0105

AC:

2635

AN:

250992

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.00888

AC:

12975

AN:

1461880

Hom.:

109

Cov.:

AF XY:

0.00949

AC XY:

6901

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00660

AC:

295

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

506

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0182

AC:

1569

AN:

86256

European-Finnish (FIN)

AF:

0.0116

AC:

620

AN:

53408

Middle Eastern (MID)

AF:

0.0270

AC:

156

AN:

5768

European-Non Finnish (NFE)

AF:

0.00825

AC:

9172

AN:

1112012

Other (OTH)

AF:

0.0102

AC:

614

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1000

1999

2999

3998

4998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.00791

AC:

1205

AN:

152350

Hom.:

Cov.:

AF XY:

0.00807

AC XY:

601

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41580

American (AMR)

AF:

0.00745

AC:

114

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0174

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0131

AC:

139

AN:

10628

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00994

AC:

676

AN:

68026

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00940

Hom.:

Bravo

AF:

0.00720

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.0109

AC:

1327

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0131

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycine encephalopathy (7)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Benign

0.092

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.19

PhyloP100

2.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.44

Sift

Benign

0.66

Sift4G

Benign

0.80

Polyphen

0.019

Vest4

0.18

MPC

0.23

ClinPred

0.0099

GERP RS

3.6

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.62

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over