NM_020806.5:c.800A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/17 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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

GPHN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 466213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHN	NM_020806.5 link	c.800A>G	p.Asn267Ser	missense_variant	Exon 8 of 23	ENST00000478722.6	NP_065857.1	Q9NQX3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6 link	c.800A>G	p.Asn267Ser	missense_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.00653

AC:

1641

AN:

251212

AF XY:

0.00664

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 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

African (AFR)

AF:

0.00141

AC:

AN:

33402

American (AMR)

AF:

0.00739

AC:

330

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00525

AC:

137

AN:

26088

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39662

South Asian (SAS)

AF:

0.00488

AC:

420

AN:

86152

European-Finnish (FIN)

AF:

0.00983

AC:

525

AN:

53396

Middle Eastern (MID)

AF:

0.0193

AC:

111

AN:

5760

European-Non Finnish (NFE)

AF:

0.00751

AC:

8310

AN:

1106752

Other (OTH)

AF:

0.00813

AC:

490

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

500

1000

1501

2001

2501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152294

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41568

American (AMR)

AF:

0.0110

AC:

168

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00650

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00775

AC:

527

AN:

68022

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00738

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

Feb 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GPHN: BP4, BS2 -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 31, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 08, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GPHN-related disorder

Benign:1

Sep 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.30

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

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over