rs776256380

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000390.4(CHM):c.715C>T(p.Arg239*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CHM
NM_000390.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.28

Publications

12 publications found

Variant links:

Genes affected

CHM (HGNC:1940): (CHM Rab escort protein) This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane. Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

CHM Gene-Disease associations (from GenCC):

choroideremia
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina

CHM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-85958965-G-A is Pathogenic according to our data. Variant chrX-85958965-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 285756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4 link	c.715C>T	p.Arg239*	stop_gained	Exon 6 of 15	ENST00000357749.7	NP_000381.1	P24386-1A8K545

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7 link	c.715C>T	p.Arg239*	stop_gained	Exon 6 of 15	1	NM_000390.4	ENSP00000350386.2		P24386-1
CHM	ENST00000467744.2 link	n.126+68526C>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182788

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097105

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362595

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26380

American (AMR)

AF:

0.00

AC:

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19348

East Asian (EAS)

AF:

0.00

AC:

AN:

30149

South Asian (SAS)

AF:

0.00

AC:

AN:

54043

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841397

Other (OTH)

AF:

0.00

AC:

AN:

46028

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg239*) in the CHM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHM are known to be pathogenic (PMID: 9067750, 23811034). This variant is present in population databases (rs776256380, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with choroideremia (PMID: 12827496, 16087855, 23811034, 26133251; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 285756). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R239X nonsense variant has been reported previously in association with choroideremia (Francis et al., 2005; Jolly et al., 2015). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we consider this variant to be pathogenic. -

Choroideremia

Pathogenic:4

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000285756 / PMID: 16087855). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2013

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.97

PhyloP100

7.3

Vest4

0.89

GERP RS

3.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over