rs10514

chr15-72209800-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002654.6(PKM):c.438C>T(p.Asn146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 1,613,704 control chromosomes in the GnomAD database, including 4,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (325 hom., cov: 31)
  • Exomes 𝑓: 0.073 (4253 hom.)
• Consequence: PKM NM_002654.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.607

Genes affected

PKM (HGNC:9021): (pyruvate kinase M1/2) This gene encodes a protein involved in glycolysis. The encoded protein is a pyruvate kinase that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate to ADP, generating ATP and pyruvate. This protein has been shown to interact with thyroid hormone and may mediate cellular metabolic effects induced by thyroid hormones. This protein has been found to bind Opa protein, a bacterial outer membrane protein involved in gonococcal adherence to and invasion of human cells, suggesting a role of this protein in bacterial pathogenesis. Several alternatively spliced transcript variants encoding a few distinct isoforms have been reported. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-72209800-G-A is Benign according to our data. Variant chr15-72209800-G-A is described in ClinVar as [Benign]. Clinvar id is 403311.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.607 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKM	NM_002654.6	c.438C>T	p.Asn146=	synonymous_variant	5/11	ENST00000335181.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKM	ENST00000335181.10	c.438C>T	p.Asn146=	synonymous_variant	5/11	1	NM_002654.6	P4

Frequencies

GnomAD3 genomes AF: 0.0604 AC: 9178 AN: 151930 Hom.: 324 Cov.: 31

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0642

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0780

Gnomad OTH AF: 0.0709

GnomAD3 exomes AF: 0.0610 AC: 15331 AN: 251492 Hom.: 569 AF XY: 0.0613 AC XY: 8334 AN XY: 135920

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.0409

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0296

Gnomad FIN exome AF: 0.0866

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0727 AC: 106333 AN: 1461656 Hom.: 4253 Cov.: 32 AF XY: 0.0713 AC XY: 51872 AN XY: 727134

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.0432

Gnomad4 ASJ exome AF: 0.0828

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0893

Gnomad4 NFE exome AF: 0.0800

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.0604 AC: 9183 AN: 152048 Hom.: 325 Cov.: 31 AF XY: 0.0599 AC XY: 4450 AN XY: 74316

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.0641

Gnomad4 ASJ AF: 0.0842

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0293

Gnomad4 FIN AF: 0.0855

Gnomad4 NFE AF: 0.0780

Gnomad4 OTH AF: 0.0697

Alfa AF: 0.0738 Hom.: 178

Bravo AF: 0.0577

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0803

EpiControl AF: 0.0840

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.081
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs10514; hg19: chr15-72502141;