rs143957574

chr8-43103568-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_032237.5(POMK):c.20A>G(p.Asn7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,612,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (1 hom.)
• Consequence: POMK NM_032237.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.109

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043215454).
• BP6: Variant 8-43103568-A-G is Benign according to our data. Variant chr8-43103568-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432418.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000748 (113/151088) while in subpopulation AFR AF= 0.00263 (108/41128). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMK	NM_032237.5	c.20A>G	p.Asn7Ser	missense_variant	4/5	ENST00000331373.10
POMK	NM_001277971.2	c.20A>G	p.Asn7Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMK	ENST00000331373.10	c.20A>G	p.Asn7Ser	missense_variant	4/5	2	NM_032237.5	P1

Frequencies

GnomAD3 genomes AF: 0.000748 AC: 113 AN: 150970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000148

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 250966 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135652

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.000260

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: 0.0000177

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.0000839 AC XY: 61 AN XY: 727248

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000748 AC: 113 AN: 151088 Hom.: 0 Cov.: 32 AF XY: 0.000623 AC XY: 46 AN XY: 73780

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000224 Hom.: 1

Bravo AF: 0.000895

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.8
Dann	Benign	0.36
DEOGEN2	Benign	0.0014	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.49	T;T;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.15
MVP		0.61
MPC		0.067
ClinPred		0.0059	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.014
gMVP		0.22

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: rs143957574; hg19: chr8-42958711;