rs782196174

Variant names:

• chrX-101398538-C-G
• rs782196174
• NM_000169.3:c.831G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PM1 PP2 PP3 BS1 BS2

The NM_000169.3(GLA):​c.831G>C​(p.Trp277Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000972 in 1,203,632 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. W277G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 39 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.05
• Publications: 1 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 -4 ACMG points.

• PM1: In a hotspot region, there are 46 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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. GnomAdExome4 allele frequency = 0.000105 (115/1092293) while in subpopulation NFE AF = 0.000137 (115/836788). AF 95% confidence interval is 0.000116. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 39 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.831G>C	p.Trp277Cys	missense	Exon 6 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.954G>C	p.Trp318Cys	missense	Exon 7 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.831G>C	p.Trp277Cys	missense	Exon 6 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.831G>C	p.Trp277Cys	missense	Exon 6 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3081C>G		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.954G>C	p.Trp318Cys	missense	Exon 7 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111339 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000377

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 115 AN: 1092293 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 39 AN XY: 357743

African (AFR) AF: 0.00 AC: 0 AN: 26300

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 53997

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.000137 AC: 115 AN: 836788

Other (OTH) AF: 0.00 AC: 0 AN: 45896

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111339 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33565

African (AFR) AF: 0.00 AC: 0 AN: 30566

American (AMR) AF: 0.00 AC: 0 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5969

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53077

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Fabry disease (4)
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.37		Gain of loop (P = 0.1069)
MVP		0.96
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99
Mutation Taster		=46/54	disease causing

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: rs782196174; hg19: chrX-100653526;