rs117632349

Variant names:

• chr8-43103459-A-G
• rs117632349
• NM_032237.5:c.-21-69A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032237.5(POMK):​c.-21-69A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00903 in 1,469,466 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (85 hom.)
• Consequence: POMK NM_032237.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0470
• Publications: 0 publications found

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]

POMK Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• limb-girdle muscular dystrophy due to POMK deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 8-43103459-A-G is Benign according to our data. Variant chr8-43103459-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1215652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00822 (1251/152270) while in subpopulation NFE AF = 0.00875 (595/68006). AF 95% confidence interval is 0.00817. There are 12 homozygotes in GnomAd4. There are 691 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032237.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMK	NM_032237.5	MANE Select	c.-21-69A>G		intron	N/A	NP_115613.1	Q9H5K3
	POMK	NM_001277971.2		c.-21-69A>G		intron	N/A	NP_001264900.1	Q9H5K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMK	ENST00000331373.10	TSL:2 MANE Select	c.-21-69A>G		intron	N/A	ENSP00000331258.5	Q9H5K3
	POMK	ENST00000676193.1		c.-21-69A>G		intron	N/A	ENSP00000502774.1	Q9H5K3
	POMK	ENST00000936358.1		c.-21-69A>G		intron	N/A	ENSP00000606417.1

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152152 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00876

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00912 AC: 12019 AN: 1317196 Hom.: 85 AF XY: 0.00921 AC XY: 6050 AN XY: 656940

African (AFR) AF: 0.00142 AC: 43 AN: 30180

American (AMR) AF: 0.00444 AC: 182 AN: 40968

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 457 AN: 22694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38902

South Asian (SAS) AF: 0.00458 AC: 353 AN: 77068

European-Finnish (FIN) AF: 0.0307 AC: 1584 AN: 51530

Middle Eastern (MID) AF: 0.0227 AC: 96 AN: 4226

European-Non Finnish (NFE) AF: 0.00883 AC: 8804 AN: 996606

Other (OTH) AF: 0.00909 AC: 500 AN: 55022

GnomAD4 genome AF: 0.00822 AC: 1251 AN: 152270 Hom.: 12 Cov.: 32 AF XY: 0.00928 AC XY: 691 AN XY: 74446

African (AFR) AF: 0.00123 AC: 51 AN: 41552

American (AMR) AF: 0.00667 AC: 102 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4824

European-Finnish (FIN) AF: 0.0374 AC: 397 AN: 10616

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 68006

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00799 Hom.: 2

Bravo AF: 0.00615

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.97
DANN	Benign	0.25
PhyloP100		0.047
PromoterAI		0.0078	Neutral
Mutation Taster		=100/0	polymorphism

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: rs117632349; hg19: chr8-42958602;