NM_000390.4:c.351A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000390.4(CHM):c.351A>G(p.Ala117Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,205,819 control chromosomes in the GnomAD database, including 22,704 homozygotes. There are 87,776 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 1547 hom., 5119 hem., cov: 22)

Exomes 𝑓: 0.23 ( 21157 hom. 82657 hem. )

Consequence

CHM
NM_000390.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.34

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant X-85964016-T-C is Benign according to our data. Variant chrX-85964016-T-C is described in ClinVar as Benign. ClinVar VariationId is 255991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4 link	c.351A>G	p.Ala117Ala	synonymous_variant	Exon 5 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.351A>G	p.Ala117Ala	synonymous_variant	Exon 5 of 15	1	NM_000390.4	ENSP00000350386.2		P24386-1
CHM	ENST00000467744.2 link	n.126+63475A>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

18728

AN:

110125

Hom.:

1549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.336

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0875

Gnomad FIN

AF:

0.163

Gnomad MID

AF:

0.260

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.187

AC:

33772

AN:

180276

AF XY:

0.189

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.232

AC:

254083

AN:

1095643

Hom.:

21157

Cov.:

AF XY:

0.229

AC XY:

82657

AN XY:

361249

show subpopulations

African (AFR)

AF:

0.0330

AC:

868

AN:

26333

American (AMR)

AF:

0.137

AC:

4787

AN:

34978

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

5074

AN:

19297

East Asian (EAS)

AF:

0.147

AC:

4439

AN:

30188

South Asian (SAS)

AF:

0.0962

AC:

5154

AN:

53584

European-Finnish (FIN)

AF:

0.187

AC:

7582

AN:

40469

Middle Eastern (MID)

AF:

0.223

AC:

920

AN:

4118

European-Non Finnish (NFE)

AF:

0.256

AC:

215456

AN:

840669

Other (OTH)

AF:

0.213

AC:

9803

AN:

46007

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6685

13370

20054

26739

33424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7462

14924

22386

29848

37310

<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:

0.170

AC:

18722

AN:

110176

Hom.:

1547

Cov.:

AF XY:

0.158

AC XY:

5119

AN XY:

32418

show subpopulations

African (AFR)

AF:

0.0351

AC:

1069

AN:

30444

American (AMR)

AF:

0.159

AC:

1629

AN:

10228

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

667

AN:

2619

East Asian (EAS)

AF:

0.109

AC:

381

AN:

3481

South Asian (SAS)

AF:

0.0866

AC:

221

AN:

2552

European-Finnish (FIN)

AF:

0.163

AC:

939

AN:

5754

Middle Eastern (MID)

AF:

0.257

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.251

AC:

13244

AN:

52727

Other (OTH)

AF:

0.196

AC:

292

AN:

1488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

535

1070

1606

2141

2676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.218

Hom.:

2010

Bravo

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Choroideremia

Benign:2

Nov 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.5

(source)

DANN

Benign

0.62

PhyloP100

1.3

Mutation Taster

=297/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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