X-101400689-G-C

Variant names:

• chrX-101400689-G-C
• rs730880448
• NM_000169.3:c.616C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000169.3(GLA):​c.616C>G​(p.Leu206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,175,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L206F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.492
• Publications: 2 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 7 ACMG points.

• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101400688-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4087437.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.

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.616C>G	p.Leu206Val	missense	Exon 4 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.739C>G	p.Leu247Val	missense	Exon 5 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.616C>G	p.Leu206Val	missense	Exon 4 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.616C>G	p.Leu206Val	missense	Exon 4 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+5232G>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.739C>G	p.Leu247Val	missense	Exon 5 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111712 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 9.40e-7 AC: 1 AN: 1063893 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 336197

African (AFR) AF: 0.0000388 AC: 1 AN: 25770

American (AMR) AF: 0.00 AC: 0 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19145

East Asian (EAS) AF: 0.00 AC: 0 AN: 30067

South Asian (SAS) AF: 0.00 AC: 0 AN: 53184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4058

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811034

Other (OTH) AF: 0.00 AC: 0 AN: 45020

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111712 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33878

African (AFR) AF: 0.0000326 AC: 1 AN: 30694

American (AMR) AF: 0.00 AC: 0 AN: 10491

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6023

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53173

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Fabry disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Benign	0.069
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.49
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.59
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.84	P
Vest4		0.32
MutPred		0.47		Gain of sheet (P = 0.0344)
MVP		0.98
MPC		1.1
ClinPred		0.16	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.95
Mutation Taster		=63/37	polymorphism

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: rs730880448; hg19: chrX-100655677;