rs200555259

Positions:

• chr8-43122837-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_032237.5(POMK):​c.1013T>G​(p.Leu338Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000598 in 1,613,350 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: POMK NM_032237.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.00

Genes affected

POMK (HGNC:26267): (protein O-mannose kinase) This gene encodes a protein that may be involved in the presentation of the laminin-binding O-linked carbohydrate chain of alpha-dystroglycan (a-DG), which forms transmembrane linkages between the extracellular matrix and the exoskeleton. Some pathogens use this O-linked carbohydrate unit for host entry. Loss of function compound heterozygous mutations in this gene were found in a human patient affected by the Walker-Warburg syndrome (WWS) phenotype. Mice lacking this gene contain misplaced neurons (heterotopia) in some regions of the brain, possibly from defects in neuronal migration. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054236174).
• BP6: Variant 8-43122837-T-G is Benign according to our data. Variant chr8-43122837-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 474188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000401 (61/152040) while in subpopulation AMR AF= 0.00197 (30/15258). AF 95% confidence interval is 0.00142. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMK	NM_032237.5	c.1013T>G	p.Leu338Arg	missense_variant	5/5	ENST00000331373.10
POMK	NM_001277971.2	c.1013T>G	p.Leu338Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMK	ENST00000331373.10	c.1013T>G	p.Leu338Arg	missense_variant	5/5	2	NM_032237.5	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000712 AC: 178 AN: 250102 Hom.: 1 AF XY: 0.000635 AC XY: 86 AN XY: 135376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.000619 AC: 904 AN: 1461310 Hom.: 1 Cov.: 32 AF XY: 0.000589 AC XY: 428 AN XY: 726982

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000680

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152040 Hom.: 0 Cov.: 33 AF XY: 0.000485 AC XY: 36 AN XY: 74264

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00115

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12;C4015184:Limb-girdle muscular dystrophy due to POMK deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.49	T;.
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.70	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	.;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.56
MVP		0.58
MPC		0.54
ClinPred		0.097	T
GERP RS		5.3
Varity_R		0.57
gMVP		0.80

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: rs200555259; hg19: chr8-42977980;