rs10217950

Variant names:

• chrX-85964016-T-C
• rs10217950
• NM_000390.4:c.351A>G
• CHM p.Ala117Ala

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.34
• Publications: 12 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000390.4. 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
	CHM	NM_000390.4	MANE Select	c.351A>G	p.Ala117Ala	synonymous	Exon 5 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.-94A>G		5_prime_UTR	Exon 5 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.-94A>G		5_prime_UTR	Exon 5 of 15	NP_001349446.1	B4DRL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	ENST00000357749.7	TSL:1 MANE Select	c.351A>G	p.Ala117Ala	synonymous	Exon 5 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.348A>G	p.Ala116Ala	synonymous	Exon 5 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.351A>G	p.Ala117Ala	synonymous	Exon 5 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 18728 AN: 110125 Hom.: 1549 Cov.: 22

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

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

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

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

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: 54 AN: 210

European-Non Finnish (NFE) AF: 0.251 AC: 13244 AN: 52727

Other (OTH) AF: 0.196 AC: 292 AN: 1488

Alfa AF: 0.218 Hom.: 2010

Bravo AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Choroideremia (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.5
DANN	Benign	0.62
PhyloP100		1.3
Mutation Taster		=297/3	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs10217950;

hg19: chrX-85219021;

COSMIC: COSV63300735;