14-67143410-T-C

Position:

• chr14-67143410-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020806.5(GPHN):​c.1797T>C​(p.Asp599Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,610,834 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (32 hom.)
• Consequence: GPHN NM_020806.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.53

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-67143410-T-C is Benign according to our data. Variant chr14-67143410-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 466203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67143410-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0031 (472/152276) while in subpopulation SAS AF= 0.00644 (31/4816). AF 95% confidence interval is 0.00486. There are 1 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPHN	NM_020806.5	c.1797T>C	p.Asp599Asp	synonymous_variant	18/23	ENST00000478722.6	NP_065857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6	c.1797T>C	p.Asp599Asp	synonymous_variant	18/23	1	NM_020806.5	ENSP00000417901.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 471 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00379 AC: 954 AN: 251406 Hom.: 8 AF XY: 0.00431 AC XY: 585 AN XY: 135862

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00915

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00432 AC: 6298 AN: 1458558 Hom.: 32 Cov.: 27 AF XY: 0.00441 AC XY: 3203 AN XY: 725794

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00999

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.00309 AC XY: 230 AN XY: 74464

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00531

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00317

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GPHN: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2020	- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C;C4551954:Hyperekplexia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41285476; hg19: chr14-67610127; COSMIC: COSV59478061;