chr14-66508553-C-G

Position:

chr14-66508553-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_020806.5(GPHN):c.26C>G(p.Thr9Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

GPHN
NM_020806.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.94

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0118897855).

BP6

Variant 14-66508553-C-G is Benign according to our data. Variant chr14-66508553-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 466208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-66508553-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00106 (162/152370) while in subpopulation NFE AF= 0.00171 (116/68030). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPHN	NM_020806.5 linkuse as main transcript	c.26C>G	p.Thr9Ser	missense_variant	1/23	ENST00000478722.6	NP_065857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6 linkuse as main transcript	c.26C>G	p.Thr9Ser	missense_variant	1/23	1	NM_020806.5	ENSP00000417901		Q9NQX3-2

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00136

AC:

342

AN:

251468

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00108

AC:

1572

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

842

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00117

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00106

AC:

162

AN:

152370

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000288

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	GPHN: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	Jul 27, 2016	- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

GPHN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

This variant is classified as likely 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

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;.;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.069

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.

MutationTaster

Benign

0.81

D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.77

N;N;N;N

REVEL

Benign

0.047

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.74

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.18

MutPred

0.43

Gain of catalytic residue at D12 (P = 0.0024);Gain of catalytic residue at D12 (P = 0.0024);Gain of catalytic residue at D12 (P = 0.0024);Gain of catalytic residue at D12 (P = 0.0024);

MVP

0.39

MPC

0.59

ClinPred

0.048

GERP RS

4.3

Varity_R

0.13

gMVP

0.49

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