NM_015164.4:c.61-8_61-7insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr1-15716220-G-GTTTTTTTTTTTTTTTTTTTTTTTTTTTTT
• rs3830503
• NM_015164.4:c.61-8_61-7insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015164.4(PLEKHM2):​c.61-8_61-7insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000811 in 1,233,200 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.96
• Publications: 0 publications found

Genes affected

PLEKHM2 (HGNC:29131): (pleckstrin homology and RUN domain containing M2) This gene encodes a protein that binds the plus-end directed microtubule motor protein kinesin, together with the lysosomal GTPase Arl8, and is required for lysosomes to distribute away from the microtubule-organizing center. The encoded protein belongs to the multisubunit BLOC-one-related complex that regulates lysosome positioning. It binds a Salmonella effector protein called Salmonella induced filament A and is a critical host determinant in Salmonella pathogenesis. It has a domain architecture consisting of an N-terminal RPIP8, UNC-14, and NESCA (RUN) domain that binds kinesin-1 as well as the lysosomal GTPase Arl8, and a C-terminal pleckstrin homology domain that binds the Salmonella induced filament A effector protein. Naturally occurring mutations in this gene lead to abnormal localization of lysosomes, impaired autophagy flux and are associated with recessive dilated cardiomyopathy and left ventricular noncompaction. [provided by RefSeq, Feb 2017]

PLEKHM2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. 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
	PLEKHM2	NM_015164.4	MANE Select	c.61-8_61-7insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.61-8_61-7insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.61-17_61-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.61-17_61-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.61-17_61-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.11e-7 AC: 1 AN: 1233200 Hom.: 0 Cov.: 20 AF XY: 0.00000162 AC XY: 1 AN XY: 616834

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26730

American (AMR) AF: 0.00 AC: 0 AN: 34536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23592

East Asian (EAS) AF: 0.00 AC: 0 AN: 36288

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 73814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 936750

Other (OTH) AF: 0.00 AC: 0 AN: 52214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-6.0

Splicing

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

Other links and lift over

dbSNP: rs3830503; hg19: chr1-16042715;