dbSNP rs145194293: AMT:p.Leu118Leu (chr3-49420328-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000481.4(AMT):c.354G>A(p.Leu118Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000823 in 1,614,170 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 16 hom. )

Consequence

AMT
NM_000481.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.0940

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.035).

BP6

Variant 3-49420328-C-T is Benign according to our data. Variant chr3-49420328-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256239.

BP7

Synonymous conserved (PhyloP=0.094 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000833 (1217/1461854) while in subpopulation MID AF = 0.0269 (155/5758). AF 95% confidence interval is 0.0235. There are 16 homozygotes in GnomAdExome4. There are 634 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 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.354G>A	p.Leu118Leu	synonymous	Exon 4 of 9	NP_000472.2
AMT	NM_001164712.2		c.354G>A	p.Leu118Leu	synonymous	Exon 4 of 10	NP_001158184.1	P48728-4
AMT	NM_001164711.2		c.186G>A	p.Leu62Leu	synonymous	Exon 3 of 8	NP_001158183.1	P48728-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMT	ENST00000273588.9	TSL:1 MANE Select	c.354G>A	p.Leu118Leu	synonymous	Exon 4 of 9	ENSP00000273588.3	P48728-1
ENSG00000283189	ENST00000636166.1	TSL:5	c.591G>A	p.Leu197Leu	synonymous	Exon 6 of 11	ENSP00000490106.1	A0A1B0GUH1
AMT	ENST00000395338.7	TSL:1	c.354G>A	p.Leu118Leu	synonymous	Exon 4 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00103

AC:

259

AN:

251464

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00843

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000747

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.000833

AC:

1217

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.000872

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00723

AC:

189

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00139

AC:

120

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0269

AC:

155

AN:

5758

European-Non Finnish (NFE)

AF:

0.000508

AC:

565

AN:

1112006

Other (OTH)

AF:

0.00204

AC:

123

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000729

AC:

111

AN:

152316

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41580

American (AMR)

AF:

0.00111

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00137

Hom.:

Bravo

AF:

0.000812

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycine encephalopathy (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.0

(source)

DANN

Benign

0.77

PhyloP100

0.094

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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