rs150226537

chr14-66508553-C-Gchr14-66508553-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: GPHN NM_020806.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.94

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 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.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPHN	ENST00000478722.6	c.26C>G	p.Thr9Ser	missense_variant	1/23	1	NM_020806.5

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152252 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00148 AC XY: 201 AN XY: 135914

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.: 1 Cov.: 30 AF XY: 0.00116 AC XY: 842 AN XY: 727194

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.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74506

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.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000866 AC: 3 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

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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 -

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

Invitae

Jan 27, 2024

- -

GPHN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2022

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Benign	0.28	T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.;.
MutationTaster	Benign	0.81	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
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	T
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

Other links and lift over

dbSNP: rs150226537; hg19: chr14-66975271;