rs41310850

Variant names:

• chr14-66965335-G-A
• rs41310850
• NM_020806.5:c.963+10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001377514.1(GPHN):​c.903+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_001377514.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.168
• Publications: 2 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: 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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377514.1. 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.963+10G>A		intron	N/A	NP_065857.1
	GPHN	NM_001377514.1		c.903+10G>A		intron	N/A	NP_001364443.1
	GPHN	NM_001377515.1		c.864+10G>A		intron	N/A	NP_001364444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.963+10G>A		intron	N/A	ENSP00000417901.1
	GPHN	ENST00000315266.9	TSL:1	c.864+10G>A		intron	N/A	ENSP00000312771.5
	GPHN	ENST00000960384.1		c.1077+10G>A		intron	N/A	ENSP00000630443.1

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

GnomAD2 exomes AF: 0.0110 AC: 2761 AN: 251318 AF XY: 0.0116

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.: 30 AF XY: 0.0133 AC XY: 9664 AN XY: 726514

African (AFR) AF: 0.00218 AC: 73 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: 2 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: 97 AN: 5766

European-Non Finnish (NFE) AF: 0.0148 AC: 16473 AN: 1110482

Other (OTH) AF: 0.0106 AC: 639 AN: 60332

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

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: 77 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.0148 AC: 156 AN: 10564

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 996 AN: 68012

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0133 Hom.: 9

Bravo AF: 0.00878

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.17
Mutation Taster		=100/0	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: rs41310850; hg19: chr14-67432052;