rs3759753

chr14-66681098-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020806.5(GPHN):c.65-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,511,636 control chromosomes in the GnomAD database, including 41,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (11976 hom., cov: 32)
  • Exomes 𝑓: 0.17 (29859 hom.)
• Consequence: GPHN NM_020806.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009337
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.180

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-66681098-T-C is Benign according to our data. Variant chr14-66681098-T-C is described in ClinVar as [Benign]. Clinvar id is 261355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPHN	NM_020806.5	c.65-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000478722.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPHN	ENST00000478722.6	c.65-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020806.5

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49694 AN: 151820 Hom.: 11937 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.315

GnomAD3 exomes AF: 0.266 AC: 66311 AN: 249382 Hom.: 12298 AF XY: 0.251 AC XY: 33872 AN XY: 134976

Gnomad AFR exome AF: 0.666

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.464

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.173 AC: 234606 AN: 1359698 Hom.: 29859 Cov.: 24 AF XY: 0.175 AC XY: 119238 AN XY: 682310

Gnomad4 AFR exome AF: 0.660

Gnomad4 AMR exome AF: 0.421

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.328 AC: 49798 AN: 151938 Hom.: 11976 Cov.: 32 AF XY: 0.331 AC XY: 24592 AN XY: 74314

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.318

Alfa AF: 0.188 Hom.: 4309

Bravo AF: 0.361

Asia WGS AF: 0.401 AC: 1391 AN: 3470

EpiCase AF: 0.155

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2019

- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.6
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.024
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: rs3759753; hg19: chr14-67147816; COSMIC: COSV59475721;