8-43097519-TAAAG-T

Position:

• chr8-43097519-TAAAG-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BA1

The NM_032237.5(POMK):​c.-209-1_-207delGAAA variant causes a splice acceptor, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 152,194 control chromosomes in the GnomAD database, including 70 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMK NM_032237.5 splice_acceptor, 5_prime_UTR, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.26

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 2.1, offset of 2, new splice context is: tgtgtgaaacacttaaaaAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 8-43097519-TAAAG-T is Benign according to our data. Variant chr8-43097519-TAAAG-T is described in ClinVar as [Benign]. Clinvar id is 420190.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMK	NM_032237.5	c.-209-1_-207delGAAA		splice_region_variant	2/5	ENST00000331373.10	NP_115613.1
POMK	NM_032237.5	c.-209-1_-207delGAAA		splice_acceptor_variant, 5_prime_UTR_variant, intron_variant	2/5	ENST00000331373.10	NP_115613.1
POMK	NM_032237.5	c.-209-1_-207delGAAA		non_coding_transcript_variant		ENST00000331373.10	NP_115613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMK	ENST00000331373.10	c.-209-4_-209-1delAAAG		splice_acceptor_variant, splice_region_variant, intron_variant		2	NM_032237.5	ENSP00000331258.5

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2443 AN: 152076 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0129

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 AFR exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0161 AC: 2447 AN: 152194 Hom.: 70 Cov.: 32 AF XY: 0.0160 AC XY: 1190 AN XY: 74414

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0119 Hom.: 6

Bravo AF: 0.0191

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, flagged submission

clinical testing

GeneDx

Nov 28, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.71		Position offset: 11
DS_AL_spliceai		0.87		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149140769; hg19: chr8-42952662;