rs10138824

Positions:

• chr14-67322840-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022474.4(PALS1):​c.1741-862G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,044 control chromosomes in the GnomAD database, including 3,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (3172 hom., cov: 32)
• Consequence: PALS1 NM_022474.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78

Genes affected

PALS1 (HGNC:18669): (protein associated with LIN7 1, MAGUK p55 family member) This gene encodes a member of the p55-like subfamily of the membrane-associated guanylate kinase (MAGUK) gene superfamily. The encoded protein participates in the polarization of differentiating cells, has been shown to regulate myelinating Schwann cells (PMID: 20237282), and is one of the components of the Crumbs complex in the retina. Mice which express lower levels of the orthologous protein have retinal degeneration and impaired vision (PMID: 22114289). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GPHN (HGNC:):

ATP6V1D (HGNC:13527): (ATPase H+ transporting V1 subunit D) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene encodes the V1 domain D subunit protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALS1	NM_022474.4	c.1741-862G>A		intron_variant		ENST00000261681.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALS1	ENST00000261681.9	c.1741-862G>A		intron_variant		1	NM_022474.4	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22664 AN: 151926 Hom.: 3164 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.0541

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22704 AN: 152044 Hom.: 3172 Cov.: 32 AF XY: 0.155 AC XY: 11548 AN XY: 74316

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.0668

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.0541

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.149

Alfa AF: 0.102 Hom.: 297

Bravo AF: 0.169

Asia WGS AF: 0.293 AC: 1024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	10
DANN	Benign	0.38

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: rs10138824; hg19: chr14-67789557;