NM_000481.4:c.635T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000481.4(AMT):c.635T>C(p.Val212Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,613,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

AMT
NM_000481.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10

Conservation

PhyloP100: 8.91

Publications

4 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

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.635T>C	p.Val212Ala	missense	Exon 6 of 9	NP_000472.2
AMT	NM_001164712.2		c.635T>C	p.Val212Ala	missense	Exon 6 of 10	NP_001158184.1	P48728-4
AMT	NM_001164710.2		c.503T>C	p.Val168Ala	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.635T>C	p.Val212Ala	missense	Exon 6 of 9	ENSP00000273588.3	P48728-1
ENSG00000283189	ENST00000636166.1	TSL:5	c.872T>C	p.Val291Ala	missense	Exon 8 of 11	ENSP00000490106.1	A0A1B0GUH1
AMT	ENST00000395338.7	TSL:1	c.635T>C	p.Val212Ala	missense	Exon 6 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes

AF:

0.000264

AC:

AN:

151634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000303

AC:

AN:

250906

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000366

AC:

535

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

283

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000381

AC:

424

AN:

1112002

Other (OTH)

AF:

0.000364

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000264

AC:

AN:

151634

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41218

American (AMR)

AF:

0.000329

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67920

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000376

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycine encephalopathy (5)

Glycine encephalopathy 2 (2)

not provided (2)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.5

PhyloP100

8.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.94

Vest4

0.81

MVP

0.88

MPC

0.84

ClinPred

0.45

GERP RS

5.4

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.83

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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