14-67279249-G-A

Position:

• chr14-67279249-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001256550.2(PALS1):​c.-23-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PALS1 NM_001256550.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71

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]

PALS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1490135 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 2, new splice context is: ttgatcttgcatcaccaaAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALS1	NM_022474.4	c.79G>A	p.Glu27Lys	missense_variant	3/15	ENST00000261681.9	NP_071919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALS1	ENST00000261681.9	c.79G>A	p.Glu27Lys	missense_variant	3/15	1	NM_022474.4	ENSP00000261681.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250704 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.79G>A (p.E27K) alteration is located in exon 3 (coding exon 1) of the MPP5 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the glutamic acid (E) at amino acid position 27 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.030	N;D
REVEL	Benign	0.22
Sift	Benign	0.074	T;D
Sift4G	Benign	0.44	T;D
Polyphen		0.30	B;D
Vest4		0.52
MVP		0.59
MPC		0.36
ClinPred		0.41	T
GERP RS		5.8
Varity_R		0.25
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs771854724; hg19: chr14-67745966;