rs7946

Variant names:

• chr17-17506246-C-T
• rs7946
• NM_148172.3:c.634G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148172.3(PEMT):​c.634G>A​(p.Val212Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,577,234 control chromosomes in the GnomAD database, including 385,160 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28593 hom., cov: 34)
  • Exomes 𝑓: 0.70 (356567 hom.)
• Consequence: PEMT NM_148172.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0910
• Publications: 130 publications found

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]

ENSG00000286430 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2130116E-6).
• BP6: Variant 17-17506246-C-T is Benign according to our data. Variant chr17-17506246-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEMT	NM_148172.3	c.634G>A	p.Val212Met	missense_variant	Exon 6 of 7	ENST00000255389.10	NP_680477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEMT	ENST00000255389.10	c.634G>A	p.Val212Met	missense_variant	Exon 6 of 7	1	NM_148172.3	ENSP00000255389.5

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89759 AN: 152044 Hom.: 28586 Cov.: 34

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.598

GnomAD2 exomes AF: 0.588 AC: 114871 AN: 195430 AF XY: 0.591

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.629

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.701

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.697 AC: 992607 AN: 1425072 Hom.: 356567 Cov.: 36 AF XY: 0.691 AC XY: 487337 AN XY: 705752

African (AFR) AF: 0.372 AC: 12184 AN: 32724

American (AMR) AF: 0.548 AC: 21942 AN: 40062

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 16018 AN: 25462

East Asian (EAS) AF: 0.240 AC: 9167 AN: 38212

South Asian (SAS) AF: 0.484 AC: 39465 AN: 81480

European-Finnish (FIN) AF: 0.701 AC: 35242 AN: 50260

Middle Eastern (MID) AF: 0.521 AC: 2980 AN: 5722

European-Non Finnish (NFE) AF: 0.748 AC: 817192 AN: 1092206

Other (OTH) AF: 0.652 AC: 38417 AN: 58944

GnomAD4 genome AF: 0.590 AC: 89804 AN: 152162 Hom.: 28593 Cov.: 34 AF XY: 0.585 AC XY: 43491 AN XY: 74394

African (AFR) AF: 0.390 AC: 16173 AN: 41522

American (AMR) AF: 0.568 AC: 8686 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2167 AN: 3470

East Asian (EAS) AF: 0.187 AC: 963 AN: 5160

South Asian (SAS) AF: 0.472 AC: 2279 AN: 4826

European-Finnish (FIN) AF: 0.700 AC: 7426 AN: 10604

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50067 AN: 67964

Other (OTH) AF: 0.597 AC: 1261 AN: 2112

Alfa AF: 0.683 Hom.: 165381

Bravo AF: 0.572

TwinsUK AF: 0.752 AC: 2788

ALSPAC AF: 0.764 AC: 2943

ESP6500AA AF: 0.406 AC: 1784

ESP6500EA AF: 0.723 AC: 6195

ExAC AF: 0.551 AC: 64902

Asia WGS AF: 0.379 AC: 1320 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17391797, 16051693, 29083408, 31695245) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.80
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.29	T;T
MetaRNN	Benign	0.0000022	T;T
MetaSVM	Benign	-0.97	T
PhyloP100		0.091
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.069
Sift	Benign	0.54	T;T
Sift4G	Benign	0.29	T;T
Vest4		0.040
ClinPred		0.021	T
GERP RS		2.2
Varity_R		0.10
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7946; hg19: chr17-17409560; COSMIC: COSV55131323; COSMIC: COSV55131323;