14-66681169-G-T

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.127G>T(p.Val43Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,585,048 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V43I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0079 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 108 hom. )

Consequence

GPHN
NM_020806.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.38

Publications

12 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=0.009079188).

BP6

Variant 14-66681169-G-T is Benign according to our data. Variant chr14-66681169-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00795 (1209/152156) while in subpopulation NFE AF = 0.0135 (920/67962). AF 95% confidence interval is 0.0128. There are 7 homozygotes in GnomAd4. There are 537 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHN	NM_020806.5 link	c.127G>T	p.Val43Leu	missense_variant	Exon 2 of 23	ENST00000478722.6	NP_065857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6 link	c.127G>T	p.Val43Leu	missense_variant	Exon 2 of 23	1	NM_020806.5	ENSP00000417901.1

Frequencies

GnomAD3 genomes

AF:

0.00795

AC:

1209

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00435

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00741

AC:

1857

AN:

250762

AF XY:

0.00778

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00475

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00933

GnomAD4 exome

AF:

0.0106

AC:

15194

AN:

1432892

Hom.:

108

Cov.:

AF XY:

0.0104

AC XY:

7436

AN XY:

714698

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

32786

American (AMR)

AF:

0.00392

AC:

175

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

360

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.00169

AC:

145

AN:

85550

European-Finnish (FIN)

AF:

0.00465

AC:

247

AN:

53104

Middle Eastern (MID)

AF:

0.00202

AC:

AN:

4946

European-Non Finnish (NFE)

AF:

0.0125

AC:

13621

AN:

1087052

Other (OTH)

AF:

0.00995

AC:

591

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

609

1217

1826

2434

3043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.00795

AC:

1209

AN:

152156

Hom.:

Cov.:

AF XY:

0.00722

AC XY:

537

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41530

American (AMR)

AF:

0.00576

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00435

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

920

AN:

67962

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00951

Hom.:

Bravo

AF:

0.00787

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.00755

AC:

917

EpiCase

AF:

0.0113

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GPHN: BS1, BS2

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 22, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

not specified

Benign:1

Jan 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GPHN c.127G>T (p.Val43Leu) results in a conservative amino acid change located in the MoaB/Mog domain (IPR001453) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0074 in 250762 control chromosomes, predominantly at a frequency of 0.012 within the Non-Finnish European subpopulation in the gnomAD database, including 10 homozygotes. The variant, c.127G>T, has not been reported in the literature in individuals affected with Sulfite Oxidase Deficiency Due To Molybdenum Cofactor Deficiency Type C, however, it was found in heterozygous state in 10 / 558 unrelated Autism Spectrum Disorder (ASD) patients (Lionel_2013), i.e. with an allele frequency of 0.009, which is comparable to the allele frequency in the general population. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) have classified the variant as benign (n=1) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.47

T;.;.;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0091

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.18

N;N;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.92

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Vest4

0.70

ClinPred

0.018

GERP RS

5.1

Varity_R

0.46

gMVP

0.80

Mutation Taster

=93/7

polymorphism

(source)

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

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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