rs144247888

Variant names:

• chr14-66681128-A-G
• rs144247888
• NM_020806.5:c.86A>G

Variant summary

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

The NM_020806.5(GPHN):​c.86A>G​(p.Asn29Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,595,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: GPHN NM_020806.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 8.59
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.86A>G	p.Asn29Ser	missense	Exon 2 of 23	NP_065857.1	Q9NQX3-2
	GPHN	NM_001377514.1		c.86A>G	p.Asn29Ser	missense	Exon 2 of 25	NP_001364443.1
	GPHN	NM_001377515.1		c.86A>G	p.Asn29Ser	missense	Exon 2 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.86A>G	p.Asn29Ser	missense	Exon 2 of 23	ENSP00000417901.1	Q9NQX3-2
	GPHN	ENST00000315266.9	TSL:1	c.86A>G	p.Asn29Ser	missense	Exon 2 of 22	ENSP00000312771.5	Q9NQX3-1
	GPHN	ENST00000960384.1		c.86A>G	p.Asn29Ser	missense	Exon 2 of 25	ENSP00000630443.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000838 AC: 21 AN: 250658 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000610 AC: 88 AN: 1443432 Hom.: 0 Cov.: 27 AF XY: 0.0000612 AC XY: 44 AN XY: 719406

African (AFR) AF: 0.0000304 AC: 1 AN: 32844

American (AMR) AF: 0.0000895 AC: 4 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39482

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.000585 AC: 3 AN: 5124

European-Non Finnish (NFE) AF: 0.0000611 AC: 67 AN: 1096672

Other (OTH) AF: 0.000151 AC: 9 AN: 59738

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74306

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000262 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.40	N
PhyloP100		8.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.18	T
Sift4G	Benign	0.47	T
Polyphen		0.25	B
Vest4		0.79
MVP		0.73
MPC		1.4
ClinPred		0.32	T
GERP RS		5.1
Varity_R		0.33
gMVP		0.49
Mutation Taster		=73/27	polymorphism

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: rs144247888; hg19: chr14-67147846;