14-66726305-A-G

Variant names:

• chr14-66726305-A-G
• rs17836572
• NM_020806.5:c.143+45120A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020806.5(GPHN):​c.143+45120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,062 control chromosomes in the GnomAD database, including 11,502 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (11502 hom., cov: 33)
• Consequence: GPHN NM_020806.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430
• Publications: 6 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC124903332 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	NM_020806.5	MANE Select	c.143+45120A>G		intron	N/A	NP_065857.1	Q9NQX3-2
	GPHN	NM_001377514.1		c.143+45120A>G		intron	N/A	NP_001364443.1
	GPHN	NM_001377515.1		c.143+45120A>G		intron	N/A	NP_001364444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.143+45120A>G		intron	N/A	ENSP00000417901.1	Q9NQX3-2
	GPHN	ENST00000315266.9	TSL:1	c.143+45120A>G		intron	N/A	ENSP00000312771.5	Q9NQX3-1
	GPHN	ENST00000960384.1		c.143+45120A>G		intron	N/A	ENSP00000630443.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47732 AN: 151944 Hom.: 11471 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47820 AN: 152062 Hom.: 11502 Cov.: 33 AF XY: 0.317 AC XY: 23599 AN XY: 74350

African (AFR) AF: 0.648 AC: 26851 AN: 41442

American (AMR) AF: 0.373 AC: 5707 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3470

East Asian (EAS) AF: 0.463 AC: 2389 AN: 5160

South Asian (SAS) AF: 0.319 AC: 1537 AN: 4818

European-Finnish (FIN) AF: 0.143 AC: 1519 AN: 10598

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.121 AC: 8213 AN: 67974

Other (OTH) AF: 0.298 AC: 630 AN: 2114

Alfa AF: 0.251 Hom.: 1626

Bravo AF: 0.348

Asia WGS AF: 0.368 AC: 1272 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.0
DANN	Benign	0.92
PhyloP100		-0.043
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17836572; hg19: chr14-67193023;