rs148158093

Variant names:

• chrX-101403828-G-A
• rs148158093
• NM_000169.3:c.352C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PP2 PP3 BS1_Supporting BS2

The NM_000169.3(GLA):​c.352C>T​(p.Arg118Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,209,304 control chromosomes in the GnomAD database, including 2 homozygotes. There are 219 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00063 (1 hom. 206 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:21 B:3 O:1
• Conservation: PhyloP100: 2.23
• Publications: 97 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_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000169.3
• 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, 0.752
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0004 (45/112545) while in subpopulation NFE AF = 0.000676 (36/53289). AF 95% confidence interval is 0.000502. There are 1 homozygotes in GnomAd4. There are 13 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 13 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.352C>T	p.Arg118Cys	missense	Exon 2 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.475C>T	p.Arg159Cys	missense	Exon 3 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.352C>T	p.Arg118Cys	missense	Exon 2 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.352C>T	p.Arg118Cys	missense	Exon 2 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-8108G>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.475C>T	p.Arg159Cys	missense	Exon 3 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.000400 AC: 45 AN: 112545 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000224 AC: 41 AN: 183291 AF XY: 0.000207

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000626 AC: 687 AN: 1096759 Hom.: 1 Cov.: 30 AF XY: 0.000569 AC XY: 206 AN XY: 362157

African (AFR) AF: 0.000265 AC: 7 AN: 26380

American (AMR) AF: 0.000170 AC: 6 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.000770 AC: 647 AN: 840799

Other (OTH) AF: 0.000586 AC: 27 AN: 46052

GnomAD4 genome AF: 0.000400 AC: 45 AN: 112545 Hom.: 1 Cov.: 23 AF XY: 0.000375 AC XY: 13 AN XY: 34711

African (AFR) AF: 0.0000646 AC: 2 AN: 30955

American (AMR) AF: 0.000564 AC: 6 AN: 10640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00 AC: 0 AN: 2776

European-Finnish (FIN) AF: 0.000162 AC: 1 AN: 6186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000676 AC: 36 AN: 53289

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000597 Hom.: 28

Bravo AF: 0.000400

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	11	-	Fabry disease (12)
1	4	3	not provided (8)
-	2	-	Cardiomyopathy (2)
-	2	-	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	GLA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.2
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.23
MVP		0.99
MPC		1.7
ClinPred		0.84	D
GERP RS		3.9
Varity_R		0.55
gMVP		0.91
Mutation Taster		=82/18	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: rs148158093; hg19: chrX-100658816; COSMIC: COSV54508358; COSMIC: COSV54508358;