rs41285470

Positions:

chr14-66924264-A-G

Variant summary

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

The NM_020806.5(GPHN):c.800A>G(p.Asn267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.007 in 1,608,422 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 57 hom. )

Consequence

GPHN
NM_020806.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.305

Variant links:

Genes affected

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:

GPHN (HGNC:):

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=0.0040991902).

BP6

Variant 14-66924264-A-G is Benign according to our data. Variant chr14-66924264-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 466213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-66924264-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00587 (894/152294) while in subpopulation AMR AF= 0.011 (168/15292). AF 95% confidence interval is 0.00963. There are 2 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPHN	NM_020806.5 linkuse as main transcript	c.800A>G	p.Asn267Ser	missense_variant	8/23	ENST00000478722.6	NP_065857.1	Q9NQX3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6 linkuse as main transcript	c.800A>G	p.Asn267Ser	missense_variant	8/23	1	NM_020806.5	ENSP00000417901.1		Q9NQX3-2

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00775

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00653

AC:

1641

AN:

251212

Hom.:

AF XY:

0.00664

AC XY:

902

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00721

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00451

Gnomad FIN exome

AF:

0.00823

Gnomad NFE exome

AF:

0.00822

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00712

AC:

10372

AN:

1456128

Hom.:

Cov.:

AF XY:

0.00707

AC XY:

5127

AN XY:

724764

show subpopulations

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.00739

Gnomad4 ASJ exome

AF:

0.00525

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00488

Gnomad4 FIN exome

AF:

0.00983

Gnomad4 NFE exome

AF:

0.00751

Gnomad4 OTH exome

AF:

0.00813

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152294

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.00635

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.00775

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00746

Hom.:

Bravo

AF:

0.00564

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00640

AC:

777

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.00884

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GPHN: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Aug 31, 2015	- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C;C4551954:Hyperekplexia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

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. -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

GPHN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.048

DANN

Benign

0.44

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

0.32

N;N

REVEL

Benign

0.089

Sift

Benign

1.0

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.11

MVP

0.12

MPC

0.51

ClinPred

0.0018

GERP RS

-6.2

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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