14-67292565-C-A

Position:

chr14-67292565-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_022474.4(PALS1):c.422C>A(p.Ser141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0354 in 1,612,732 control chromosomes in the GnomAD database, including 1,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.029 ( 89 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1063 hom. )

Consequence

PALS1
NM_022474.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.50

Variant links:

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]

PALS1 links:

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]

GPHN links:

ENSG00000286319 (HGNC:):

ENSG00000286319 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005336106).

BP6

Variant 14-67292565-C-A is Benign according to our data. Variant chr14-67292565-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3208236.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0291 (4423/152222) while in subpopulation NFE AF= 0.0412 (2803/67996). AF 95% confidence interval is 0.0399. There are 89 homozygotes in gnomad4. There are 2190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 89 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALS1	NM_022474.4 linkuse as main transcript	c.422C>A	p.Ser141Tyr	missense_variant	4/15	ENST00000261681.9	NP_071919.2	Q8N3R9-1Q658X5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALS1	ENST00000261681.9 linkuse as main transcript	c.422C>A	p.Ser141Tyr	missense_variant	4/15	1	NM_022474.4	ENSP00000261681.4		Q8N3R9-1

Frequencies

GnomAD3 genomes

AF:

0.0290

AC:

4415

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00690

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0330

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0504

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0412

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0345

AC:

8673

AN:

251202

Hom.:

181

AF XY:

0.0345

AC XY:

4682

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00609

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.0224

Gnomad EAS exome

AF:

0.000871

Gnomad SAS exome

AF:

0.0310

Gnomad FIN exome

AF:

0.0515

Gnomad NFE exome

AF:

0.0399

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0361

AC:

52704

AN:

1460510

Hom.:

1063

Cov.:

AF XY:

0.0363

AC XY:

26346

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.0443

Gnomad4 ASJ exome

AF:

0.0252

Gnomad4 EAS exome

AF:

0.000783

Gnomad4 SAS exome

AF:

0.0328

Gnomad4 FIN exome

AF:

0.0506

Gnomad4 NFE exome

AF:

0.0380

Gnomad4 OTH exome

AF:

0.0315

GnomAD4 genome

AF:

0.0291

AC:

4423

AN:

152222

Hom.:

Cov.:

AF XY:

0.0294

AC XY:

2190

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00688

Gnomad4 AMR

AF:

0.0334

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0504

Gnomad4 NFE

AF:

0.0412

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0335

Hom.:

155

Bravo

AF:

0.0273

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0414

AC:

356

ExAC

AF:

0.0347

AC:

4209

EpiCase

AF:

0.0351

EpiControl

AF:

0.0361

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

0.018

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

N;N;D

REVEL

Benign

0.11

Sift

Benign

0.034

D;D;T

Sift4G

Uncertain

0.037

D;D;T

Polyphen

0.0050

B;.;.

Vest4

0.12

MPC

0.80

ClinPred

0.041

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over