1-15684510-GGGCGGC-GGGC

Variant names:

• chr1-15684510-GGGC-G
• rs767880122
• NM_015164.4:c.-37_-35delCGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015164.4(PLEKHM2):​c.-37_-35delCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 976,542 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (4 hom.)
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.-37_-35delCGG		5_prime_UTR_variant	Exon 1 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.-37_-35delCGG		5_prime_UTR_variant	Exon 1 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.99+2823_99+2825delCGG		intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1	c.99+2823_99+2825delCGG		intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799	c.-37_-35delCGG		5_prime_UTR_variant	Exon 1 of 20	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793	c.-37_-35delCGG		5_prime_UTR_variant	Exon 1 of 19	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.-48_-46delGGC		upstream_gene_variant				ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.-30_-28delGGC		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 367 AN: 144044 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00266

Gnomad ASJ AF: 0.00326

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.00568

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00301

GnomAD3 exomes AF: 0.000910 AC: 9 AN: 9892 Hom.: 0 AF XY: 0.00125 AC XY: 6 AN XY: 4792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00308 AC: 2568 AN: 832442 Hom.: 4 AF XY: 0.00315 AC XY: 1230 AN XY: 390400

Gnomad4 AFR exome AF: 0.00196

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.000125

Gnomad4 SAS exome AF: 0.00712

Gnomad4 FIN exome AF: 0.000437

Gnomad4 NFE exome AF: 0.00305

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00257 AC: 370 AN: 144100 Hom.: 1 Cov.: 0 AF XY: 0.00233 AC XY: 163 AN XY: 70002

Gnomad4 AFR AF: 0.00179

Gnomad4 AMR AF: 0.00266

Gnomad4 ASJ AF: 0.00326

Gnomad4 EAS AF: 0.000209

Gnomad4 SAS AF: 0.00590

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00299

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs767880122; hg19: chr1-16011005;