rs111422676

Variant names:

• chrX-101398011-C-T
• rs111422676
• NM_000169.3:c.1088G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 17P and 5B. PS3 PM1 PM5 PP2 PP5_Very_Strong BS1_Supporting BS2

The NM_000169.3(GLA):​c.1088G>A​(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,207,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000695730: "In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 9 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:2
• Conservation: PhyloP100: -0.0720
• Publications: 45 publications found

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695730: "In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity."; SCV001422922: "In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 19387866)."; SCV001588429: Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 21598360).; SCV001712060: "In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015)."; SCV002053129: Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro, with a greater than 70% decrease compared to wild type (PMID: 21598360, 23935525).; SCV005426137: Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID: 19387866, 21598360, respectively).
• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398012-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP5: Variant X-101398011-C-T is Pathogenic according to our data. Variant chrX-101398011-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 222141.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 = 0.000125 (14/111964) while in subpopulation AMR AF = 0.00133 (14/10556). AF 95% confidence interval is 0.000802. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. 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
	GLA	NM_000169.3	MANE Select	c.1088G>A	p.Arg363His	missense	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1211G>A	p.Arg404His	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2554C>T		intron	N/A	NP_001186902.2	H7BZ11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1088G>A	p.Arg363His	missense	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2554C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1211G>A	p.Arg404His	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 111964 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000545 AC: 10 AN: 183364 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1096001 Hom.: 0 Cov.: 30 AF XY: 0.0000249 AC XY: 9 AN XY: 361377

African (AFR) AF: 0.00 AC: 0 AN: 26360

American (AMR) AF: 0.0000852 AC: 3 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840094

Other (OTH) AF: 0.00 AC: 0 AN: 46021

GnomAD4 genome AF: 0.000125 AC: 14 AN: 111964 Hom.: 0 Cov.: 23 AF XY: 0.000264 AC XY: 9 AN XY: 34152

African (AFR) AF: 0.00 AC: 0 AN: 30753

American (AMR) AF: 0.00133 AC: 14 AN: 10556

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6061

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53222

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000831 Hom.: 1

Bravo AF: 0.000121

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	1	-	Fabry disease (14)
2	1	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
CardioboostCm	Benign	0.023
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	2.0	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.072
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.47	T
Sift4G	Benign	0.51	T
Polyphen		0.41	B
Vest4		0.64
MutPred		0.86		Loss of sheet (P = 0.0817)
MVP		0.98
MPC		0.90
ClinPred		0.019	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.79
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111422676; hg19: chrX-100652999;