NM_020806.5:c.963+10G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.168

Publications

2 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

GPHN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 466214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHN	NM_020806.5 link	c.963+10G>A		intron_variant	Intron 9 of 22	ENST00000478722.6	NP_065857.1	Q9NQX3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6 link	c.963+10G>A		intron_variant	Intron 9 of 22	1	NM_020806.5	ENSP00000417901.1		Q9NQX3-2

Frequencies

GnomAD3 genomes

AF:

0.00979

AC:

1488

AN:

152004

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0110

AC:

2761

AN:

251318

AF XY:

0.0116

show subpopulations

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 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.:

AF XY:

0.0133

AC XY:

9664

AN XY:

726514

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33438

American (AMR)

AF:

0.00459

AC:

205

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0275

AC:

719

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00547

AC:

472

AN:

86236

European-Finnish (FIN)

AF:

0.0125

AC:

666

AN:

53398

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0148

AC:

16473

AN:

1110482

Other (OTH)

AF:

0.0106

AC:

639

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

860

1720

2579

3439

4299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

614

1228

1842

2456

3070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00978

AC:

1487

AN:

152122

Hom.:

Cov.:

AF XY:

0.00976

AC XY:

726

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41506

American (AMR)

AF:

0.00700

AC:

107

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00436

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0148

AC:

156

AN:

10564

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

996

AN:

68012

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.00878

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over