rs113361507

Positions:

• chr8-43122830-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032237.5(POMK):​c.1006G>A​(p.Asp336Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,613,846 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (16 hom.)
• Consequence: POMK NM_032237.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.966

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036479235).
• BP6: Variant 8-43122830-G-A is Benign according to our data. Variant chr8-43122830-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00252 (383/152254) while in subpopulation SAS AF= 0.011 (53/4826). AF 95% confidence interval is 0.00862. There are 2 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMK	NM_032237.5	c.1006G>A	p.Asp336Asn	missense_variant	5/5	ENST00000331373.10
POMK	NM_001277971.2	c.1006G>A	p.Asp336Asn	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMK	ENST00000331373.10	c.1006G>A	p.Asp336Asn	missense_variant	5/5	2	NM_032237.5	P1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00169 AC: 423 AN: 250672 Hom.: 7 AF XY: 0.00185 AC XY: 251 AN XY: 135612

Gnomad AFR exome AF: 0.00704

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00918

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000775 AC: 1133 AN: 1461592 Hom.: 16 Cov.: 33 AF XY: 0.000975 AC XY: 709 AN XY: 727104

Gnomad4 AFR exome AF: 0.00639

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74434

Gnomad4 AFR AF: 0.00749

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.00232

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2019

- -

POMK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.53
DEOGEN2	Benign	0.0024	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.69	T;.
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.051
MVP		0.20
MPC		0.079
ClinPred		0.00038	T
GERP RS		-0.12
Varity_R		0.019
gMVP		0.19

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: rs113361507; hg19: chr8-42977973;