rs10217950

chrX-85964016-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000390.4(CHM):c.351A>G(p.Ala117=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 255991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-85964016-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CHM	NM_000390.4	c.351A>G	p.Ala117=	synonymous_variant	5/15	ENST00000357749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHM	ENST00000357749.7	c.351A>G	p.Ala117=	synonymous_variant	5/15	1	NM_000390.4	P1
CHM	ENST00000467744.2	n.126+63475A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.170 AC: 18728 AN: 110125 Hom.: 1549 Cov.: 22 AF XY: 0.158 AC XY: 5119 AN XY: 32355

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

GnomAD3 exomes AF: 0.187 AC: 33772 AN: 180276 Hom.: 2399 AF XY: 0.189 AC XY: 12282 AN XY: 64986

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 SAS exome AF: 0.0928

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.: 31 AF XY: 0.229 AC XY: 82657 AN XY: 361249

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0962

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.170 AC: 18722 AN: 110176 Hom.: 1547 Cov.: 22 AF XY: 0.158 AC XY: 5119 AN XY: 32418

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0866

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.196

Alfa AF: 0.218 Hom.: 2010

Bravo AF: 0.167

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Choroideremia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.5
Dann	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs10217950; hg19: chrX-85219021; COSMIC: COSV63300735;