rs10138824

Variant names:

• chr14-67322840-G-A
• rs10138824
• NM_022474.4:c.1741-862G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022474.4. 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
	PALS1	NM_022474.4	MANE Select	c.1741-862G>A		intron	N/A	NP_071919.2
	PALS1	NM_001256550.2		c.1639-862G>A		intron	N/A	NP_001243479.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALS1	ENST00000261681.9	TSL:1 MANE Select	c.1741-862G>A		intron	N/A	ENSP00000261681.4
	PALS1	ENST00000555925.5	TSL:1	c.1639-862G>A		intron	N/A	ENSP00000451488.1
	PALS1	ENST00000676464.1		c.1741-862G>A		intron	N/A	ENSP00000503713.1

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

African (AFR) AF: 0.314 AC: 13014 AN: 41450

American (AMR) AF: 0.215 AC: 3279 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.422 AC: 2180 AN: 5166

South Asian (SAS) AF: 0.262 AC: 1262 AN: 4822

European-Finnish (FIN) AF: 0.0541 AC: 572 AN: 10564

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1818 AN: 68002

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.108 Hom.: 331

Bravo AF: 0.169

Asia WGS AF: 0.293 AC: 1024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	10
DANN	Benign	0.38
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs10138824; hg19: chr14-67789557;