rs869312150

Variant names:

• chrX-101398945-G-A
• rs869312150
• NM_000169.3:c.641C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000169.3(GLA):​c.641C>T​(p.Pro214Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000918 in 1,088,937 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P214S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense, splice_region
• Scores: Splicing: ADA: 0.06452
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 6.88
• Publications: 6 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant X-101398945-G-A is Pathogenic according to our data. Variant chrX-101398945-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217392.

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.641C>T	p.Pro214Leu	missense splice_region	Exon 5 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.764C>T	p.Pro255Leu	missense splice_region	Exon 6 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.641C>T	p.Pro214Leu	missense splice_region	Exon 5 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.641C>T	p.Pro214Leu	missense splice_region	Exon 5 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3488G>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.764C>T	p.Pro255Leu	missense splice_region	Exon 6 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1088937 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 355149

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26227

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.00 AC: 0 AN: 53848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3330

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834588

Other (OTH) AF: 0.00 AC: 0 AN: 45749

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000855 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Fabry disease (3)
-	-	-	Migalastat response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Uncertain	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.85
Sift	Benign	0.045	D
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.91
MutPred		0.69		Loss of ubiquitination at K213 (P = 0.051)
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.99
Mutation Taster		=67/33	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.065
dbscSNV1_RF	Benign	0.35
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: rs869312150; hg19: chrX-100653933;