14-66508547-T-G

Variant names:

• chr14-66508547-T-G
• rs370646151
• NM_020806.5:c.20T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020806.5(GPHN):​c.20T>G​(p.Ile7Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I7T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPHN NM_020806.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12
• Publications: 0 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

ENSG00000258561 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.20T>G	p.Ile7Ser	missense	Exon 1 of 23	NP_065857.1	Q9NQX3-2
	GPHN	NM_001377514.1		c.20T>G	p.Ile7Ser	missense	Exon 1 of 25	NP_001364443.1
	GPHN	NM_001377515.1		c.20T>G	p.Ile7Ser	missense	Exon 1 of 24	NP_001364444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.20T>G	p.Ile7Ser	missense	Exon 1 of 23	ENSP00000417901.1	Q9NQX3-2
	GPHN	ENST00000315266.9	TSL:1	c.20T>G	p.Ile7Ser	missense	Exon 1 of 22	ENSP00000312771.5	Q9NQX3-1
	GPHN	ENST00000960384.1		c.20T>G	p.Ile7Ser	missense	Exon 1 of 25	ENSP00000630443.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.022	D
Polyphen		0.079	B
Vest4		0.75
MutPred		0.34		Gain of catalytic residue at D12 (P = 0.0067)
MVP		0.52
MPC		1.2
ClinPred		0.94	D
GERP RS		5.2
PromoterAI		-0.024	Neutral
Varity_R		0.64
gMVP		0.64
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370646151; hg19: chr14-66975265;