rs41310850

chr14-66965335-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020806.5(GPHN):c.963+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,612,282 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (8 hom., cov: 32)
  • Exomes 𝑓: 0.013 (171 hom.)
• Consequence: GPHN NM_020806.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.168

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=-0.77).
• BP6: Variant 14-66965335-G-A is Benign according to our data. Variant chr14-66965335-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-66965335-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00978 (1487/152122) while in subpopulation NFE AF= 0.0146 (996/68012). AF 95% confidence interval is 0.0139. There are 8 homozygotes in gnomad4. There are 726 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPHN	NM_020806.5	c.963+10G>A		intron_variant		ENST00000478722.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPHN	ENST00000478722.6	c.963+10G>A		intron_variant		1	NM_020806.5

Frequencies

GnomAD3 genomes AF: 0.00979 AC: 1488 AN: 152004 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0110 AC: 2761 AN: 251318 Hom.: 23 AF XY: 0.0116 AC XY: 1581 AN XY: 135826

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0132 AC: 19346 AN: 1460160 Hom.: 171 Cov.: 30 AF XY: 0.0133 AC XY: 9664 AN XY: 726514

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00547

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00978 AC: 1487 AN: 152122 Hom.: 8 Cov.: 32 AF XY: 0.00976 AC XY: 726 AN XY: 74360

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0132 Hom.: 7

Bravo AF: 0.00878

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2020

- -

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	-0.77
Cadd	Benign	11
Dann	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs41310850; hg19: chr14-67432052;