rs41285476

Variant names:

• chr14-67143410-T-C
• rs41285476
• NM_020806.5:c.1797T>C
• GPHN p.Asp599Asp

Your query was ambiguous. Multiple possible variants found:

• chr14-67143410-T-C
• chr14-67143410-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020806.5(GPHN):​c.1797T>C​(p.Asp599Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,610,834 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (32 hom.)
• Consequence: GPHN NM_020806.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.53
• Publications: 4 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000307479 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-67143410-T-C is Benign according to our data. Variant chr14-67143410-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0031 (472/152276) while in subpopulation SAS AF = 0.00644 (31/4816). AF 95% confidence interval is 0.00486. There are 1 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AD,AR gene

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.1797T>C	p.Asp599Asp	synonymous	Exon 18 of 23	NP_065857.1	Q9NQX3-2
	GPHN	NM_001377514.1		c.1857T>C	p.Asp619Asp	synonymous	Exon 20 of 25	NP_001364443.1
	GPHN	NM_001377515.1		c.1827T>C	p.Asp609Asp	synonymous	Exon 19 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.1797T>C	p.Asp599Asp	synonymous	Exon 18 of 23	ENSP00000417901.1	Q9NQX3-2
	GPHN	ENST00000315266.9	TSL:1	c.1698T>C	p.Asp566Asp	synonymous	Exon 17 of 22	ENSP00000312771.5	Q9NQX3-1
	GPHN	ENST00000960384.1		c.1968T>C	p.Asp656Asp	synonymous	Exon 20 of 25	ENSP00000630443.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 471 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00379 AC: 954 AN: 251406 AF XY: 0.00431

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00432 AC: 6298 AN: 1458558 Hom.: 32 Cov.: 27 AF XY: 0.00441 AC XY: 3203 AN XY: 725794

African (AFR) AF: 0.000658 AC: 22 AN: 33422

American (AMR) AF: 0.00130 AC: 58 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00999 AC: 861 AN: 86188

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53408

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00461 AC: 5117 AN: 1108986

Other (OTH) AF: 0.00267 AC: 161 AN: 60286

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.00309 AC XY: 230 AN XY: 74464

African (AFR) AF: 0.000722 AC: 30 AN: 41570

American (AMR) AF: 0.00229 AC: 35 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00531 AC: 361 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00394 Hom.: 2

Bravo AF: 0.00317

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00450

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (1)
-	-	1	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C;C4551954:Hyperekplexia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.63
PhyloP100		1.5
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41285476;

hg19: chr14-67610127;

COSMIC: COSV59478061;