Genetic Variant PEMT:p.Arg40Gln (chr17-17577005-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_148172.3(PEMT):c.119G>A(p.Arg40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PEMT
NM_148172.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.103

Publications

1 publications found

Variant links:

Genes affected

PEMT (HGNC:8830): (phosphatidylethanolamine N-methyltransferase) Phosphatidylcholine (PC) is the most abundant mammalian phospholipid. This gene encodes an enzyme which converts phosphatidylethanolamine to phosphatidylcholine by sequential methylation in the liver. Another distinct synthetic pathway in nucleated cells converts intracellular choline to phosphatidylcholine by a three-step process. The protein isoforms encoded by this gene localize to the endoplasmic reticulum and mitochondria-associated membranes. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2012]

PEMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02780813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148172.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEMT	NM_148172.3	MANE Select	c.119G>A	p.Arg40Gln	missense	Exon 2 of 7	NP_680477.1	Q9UBM1-2
PEMT	NM_001267552.2		c.119G>A	p.Arg40Gln	missense	Exon 2 of 8	NP_001254481.1	Q9UBM1-3
PEMT	NM_001267551.2		c.53G>A	p.Arg18Gln	missense	Exon 2 of 7	NP_001254480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEMT	ENST00000255389.10	TSL:1 MANE Select	c.119G>A	p.Arg40Gln	missense	Exon 2 of 7	ENSP00000255389.5	Q9UBM1-2
PEMT	ENST00000395782.5	TSL:1	c.8G>A	p.Arg3Gln	missense	Exon 2 of 7	ENSP00000379128.1	Q9UBM1-1
PEMT	ENST00000395783.5	TSL:1	c.8G>A	p.Arg3Gln	missense	Exon 2 of 7	ENSP00000379129.1	Q9UBM1-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

250986

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461638

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00114

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111910

Other (OTH)

AF:

0.0000331

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.000393

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.0000303

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.000140

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.035

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.77

M_CAP

Benign

0.0081

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.52

PhyloP100

0.10

PrimateAI

Benign

0.22

PROVEAN

Benign

0.21

REVEL

Benign

0.047

Sift

Benign

0.58

Sift4G

Benign

0.60

Polyphen

0.0020

Vest4

0.23

MVP

0.46

MPC

0.093

ClinPred

0.020

GERP RS

0.77

PromoterAI

-0.0059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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