rs869312162

Variant names:

• chrX-101398044-G-C
• rs869312162
• NM_000169.3:c.1055C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 11P and 8B. PS3 PM1 PM5 PP2 PP3_Moderate BS1 BS2

The NM_000169.3(GLA):​c.1055C>G​(p.Ala352Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003844678: The most pronounced variant effect results in approximately 54% of normal activity in-vitro (e.g., Lukas_2016). PMID:36177613". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A352V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:10 O:1
• Conservation: PhyloP100: 9.26
• Publications: 4 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: Uncertain_significance. The variant received 3 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003844678: The most pronounced variant effect results in approximately 54% of normal activity in-vitro (e.g., Lukas_2016). PMID:36177613
• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398045-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4087627.Status of the report is criteria_provided_single_submitter, 1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000364 (4/1097447) while in subpopulation MID AF = 0.000484 (2/4131). AF 95% confidence interval is 0.0000853. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.1055C>G	p.Ala352Gly	missense	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1178C>G	p.Ala393Gly	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2587G>C		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.1055C>G	p.Ala352Gly	missense	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2587G>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1178C>G	p.Ala393Gly	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183231 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000364 AC: 4 AN: 1097447 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362811

African (AFR) AF: 0.00 AC: 0 AN: 26391

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4131

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841397

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	6	-	Fabry disease (9)
-	2	-	not provided (2)
-	1	-	Intellectual disability, X-linked, syndromic, Bain type (1)
-	1	-	not specified (1)
-	-	-	Migalastat response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.66
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.98	D
Vest4		0.65
MutPred		0.55		Loss of stability (P = 0.1602)
MVP		0.92
MPC		1.5
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.97
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs869312162; hg19: chrX-100653032;