rs3784075

chr14-66824468-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.202-6T>C variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.101 in 1,515,180 control chromosomes in the GnomAD database, including 24,680 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (8271 hom., cov: 32)
  • Exomes 𝑓: 0.086 (16409 hom.)
• Consequence: GPHN NM_020806.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005558
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.31

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=-0.51).
• BP6: Variant 14-66824468-T-C is Benign according to our data. Variant chr14-66824468-T-C is described in ClinVar as [Benign]. Clinvar id is 261354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPHN	NM_020806.5	c.202-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000478722.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPHN	ENST00000478722.6	c.202-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020806.5

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35569 AN: 151870 Hom.: 8264 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.0826

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.184 AC: 45943 AN: 250310 Hom.: 8538 AF XY: 0.169 AC XY: 22823 AN XY: 135316

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.0846

Gnomad EAS exome AF: 0.461

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.0774

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.0864 AC: 117770 AN: 1363192 Hom.: 16409 Cov.: 23 AF XY: 0.0889 AC XY: 60852 AN XY: 684388

Gnomad4 AFR exome AF: 0.574

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.0843

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.234 AC: 35621 AN: 151988 Hom.: 8271 Cov.: 32 AF XY: 0.240 AC XY: 17807 AN XY: 74320

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.0821

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.0826

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.213

Alfa AF: 0.0829 Hom.: 3434

Bravo AF: 0.267

Asia WGS AF: 0.340 AC: 1182 AN: 3474

EpiCase AF: 0.0471

EpiControl AF: 0.0446

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	-0.51
Cadd	Benign	14
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.012
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: rs3784075; hg19: chr14-67291186; COSMIC: COSV59475671; COSMIC: COSV59475671;