NM_020806.5:c.65-9T>C

Variant names:

• chr14-66681098-T-C
• rs3759753
• NM_020806.5:c.65-9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020806.5(GPHN):​c.65-9T>C variant causes a 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 intron
• Scores: Splicing: ADA: 0.00009337
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.180
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020806.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	NM_020806.5	MANE Select	c.65-9T>C		intron	N/A	NP_065857.1
	GPHN	NM_001377514.1		c.65-9T>C		intron	N/A	NP_001364443.1
	GPHN	NM_001377515.1		c.65-9T>C		intron	N/A	NP_001364444.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.65-9T>C		intron	N/A	ENSP00000417901.1
	GPHN	ENST00000315266.9	TSL:1	c.65-9T>C		intron	N/A	ENSP00000312771.5
	GPHN	ENST00000543237.5	TSL:2	c.65-9T>C		intron	N/A	ENSP00000438404.1

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

GnomAD2 exomes AF: 0.266 AC: 66311 AN: 249382 AF XY: 0.251

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 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

African (AFR) AF: 0.660 AC: 19714 AN: 29878

American (AMR) AF: 0.421 AC: 18736 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6006 AN: 25408

East Asian (EAS) AF: 0.441 AC: 17142 AN: 38892

South Asian (SAS) AF: 0.302 AC: 25237 AN: 83600

European-Finnish (FIN) AF: 0.149 AC: 7825 AN: 52518

Middle Eastern (MID) AF: 0.291 AC: 1386 AN: 4758

European-Non Finnish (NFE) AF: 0.124 AC: 126456 AN: 1023580

Other (OTH) AF: 0.214 AC: 12104 AN: 56520

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

African (AFR) AF: 0.655 AC: 27090 AN: 41384

American (AMR) AF: 0.386 AC: 5886 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3466

East Asian (EAS) AF: 0.468 AC: 2418 AN: 5164

South Asian (SAS) AF: 0.326 AC: 1575 AN: 4828

European-Finnish (FIN) AF: 0.154 AC: 1630 AN: 10570

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9430 AN: 67940

Other (OTH) AF: 0.318 AC: 673 AN: 2114

Alfa AF: 0.232 Hom.: 10061

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3759753; hg19: chr14-67147816; COSMIC: COSV59475721;