X-101401654-G-T

Variant names:

• chrX-101401654-G-T
• rs782722844
• NM_000169.3:c.525C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_001406747.1(GLA):​c.648C>A​(p.Asp216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,208,878 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D216N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: GLA NM_001406747.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.23
• Publications: 8 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 2 ACMG points.

• PM1: In a hotspot region, there are 32 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001406747.1
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33320332).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406747.1. 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.525C>A	p.Asp175Glu	missense	Exon 3 of 7	NP_000160.1
	GLA	NM_001406747.1		c.648C>A	p.Asp216Glu	missense	Exon 4 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.525C>A	p.Asp175Glu	missense	Exon 3 of 6	NP_001393677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.525C>A	p.Asp175Glu	missense	Exon 3 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+6197G>T		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.648C>A	p.Asp216Glu	missense	Exon 4 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111743 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

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183473 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00000820 AC: 9 AN: 1097135 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362501

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54122

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

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841120

Other (OTH) AF: 0.0000217 AC: 1 AN: 46055

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111743 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33921

African (AFR) AF: 0.0000326 AC: 1 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 10486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6016

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53213

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Fabry disease (5)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.020
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.33	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.42
Sift	Benign	0.30	T
Sift4G	Benign	0.27	T
Polyphen		0.058	B
Vest4		0.15
MutPred		0.49		Loss of loop (P = 0.2237)
MVP		0.88
MPC		0.68
ClinPred		0.055	T
GERP RS		4.1
Varity_R		0.40
gMVP		0.92
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782722844; hg19: chrX-100656642;