chr14-67279348-C-T

Position:

chr14-67279348-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022474.4(PALS1):c.178C>T(p.Arg60Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,613,214 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 16 hom. )

Consequence

PALS1
NM_022474.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008388132).

BP6

Variant 14-67279348-C-T is Benign according to our data. Variant chr14-67279348-C-T is described in ClinVar as [Benign]. Clinvar id is 785461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00866 (1313/151588) while in subpopulation AFR AF= 0.0301 (1242/41268). AF 95% confidence interval is 0.0287. There are 21 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALS1	NM_022474.4 link	c.178C>T	p.Arg60Trp	missense_variant	3/15	ENST00000261681.9	NP_071919.2	Q8N3R9-1Q658X5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALS1	ENST00000261681.9 link	c.178C>T	p.Arg60Trp	missense_variant	3/15	1	NM_022474.4	ENSP00000261681.4		Q8N3R9-1

Frequencies

GnomAD3 genomes

AF:

0.00867

AC:

1313

AN:

151470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00283

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.00435

GnomAD3 exomes

AF:

0.00221

AC:

555

AN:

250680

Hom.:

AF XY:

0.00173

AC XY:

234

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00111

AC:

1628

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000992

AC XY:

721

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0317

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000359

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00866

AC:

1313

AN:

151588

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

629

AN XY:

74032

show subpopulations

Gnomad4 AFR

AF:

0.0301

Gnomad4 AMR

AF:

0.00283

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.00430

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00941

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0252

AC:

111

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00269

AC:

327

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;T;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.1

L;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.4

D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.46

MVP

0.45

MPC

1.0

ClinPred

0.039

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

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

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