NM_020806.5:c.127G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar 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

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:

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=0.009079188).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

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	Q9NQX3-2

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		Q9NQX3-2

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

GnomAD3 exomes

AF:

0.00741

AC:

1857

AN:

250762

Hom.:

AF XY:

0.00778

AC XY:

1055

AN XY:

135556

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 SAS exome

AF:

0.00190

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

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00465

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.00995

GnomAD4 genome

AF:

0.00795

AC:

1209

AN:

152156

Hom.:

Cov.:

AF XY:

0.00722

AC XY:

537

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00576

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00435

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.0107

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

- -

Feb 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

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;.;.

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

Polyphen

0.0060

B;B;B;B

Vest4

0.70

MutPred

0.55

Gain of catalytic residue at P46 (P = 0.0107);Gain of catalytic residue at P46 (P = 0.0107);Gain of catalytic residue at P46 (P = 0.0107);Gain of catalytic residue at P46 (P = 0.0107);

MVP

0.63

MPC

0.67

ClinPred

0.018

GERP RS

5.1

Varity_R

0.46

gMVP

0.80

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