chrX-85864658-A-AGGTTTGTGCTTT

Variant names:

• chrX-85864658-A-AGGTTTGTGCTTT
• rs767043768
• NM_000390.4:c.1922_1933dupAAAGCACAAACC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_000390.4(CHM):​c.1922_1933dupAAAGCACAAACC​(p.Asn644_Leu645insGlnSerThrAsn) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,208,303 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 85 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L645L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (0 hom. 78 hem.)
• Consequence: CHM NM_000390.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.74
• Publications: 1 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: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000390.4.
• BP6: Variant X-85864658-A-AGGTTTGTGCTTT is Benign according to our data. Variant chrX-85864658-A-AGGTTTGTGCTTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 715156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000188 (21/111515) while in subpopulation AMR AF = 0.000477 (5/10480). AF 95% confidence interval is 0.000188. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

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.1922_1933dupAAAGCACAAACC	p.Asn644_Leu645insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1478_1489dupAAAGCACAAACC	p.Asn496_Leu497insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1478_1489dupAAAGCACAAACC	p.Asn496_Leu497insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 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.1922_1933dupAAAGCACAAACC	p.Asn644_Leu645insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1919_1930dupAAAGCACAAACC	p.Asn643_Leu644insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1907_1918dupAAAGCACAAACC	p.Asn639_Leu640insGlnSerThrAsn	conservative_inframe_insertion	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111515 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.000670

GnomAD2 exomes AF: 0.000145 AC: 26 AN: 179470 AF XY: 0.000124

Gnomad AFR exome AF: 0.0000771

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000451

GnomAD4 exome AF: 0.000242 AC: 265 AN: 1096788 Hom.: 0 Cov.: 29 AF XY: 0.000215 AC XY: 78 AN XY: 362334

African (AFR) AF: 0.0000379 AC: 1 AN: 26388

American (AMR) AF: 0.000142 AC: 5 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30115

South Asian (SAS) AF: 0.00 AC: 0 AN: 53865

European-Finnish (FIN) AF: 0.0000989 AC: 4 AN: 40436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.000295 AC: 248 AN: 841353

Other (OTH) AF: 0.000152 AC: 7 AN: 46027

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111515 Hom.: 0 Cov.: 23 AF XY: 0.000208 AC XY: 7 AN XY: 33711

African (AFR) AF: 0.000131 AC: 4 AN: 30617

American (AMR) AF: 0.000477 AC: 5 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53143

Other (OTH) AF: 0.000670 AC: 1 AN: 1492

Alfa AF: 0.000162 Hom.: 1

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=85/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs767043768; hg19: chrX-85119663;