chrX-101397997-C-G

Variant names:

• chrX-101397997-C-G
• rs144994244
• NM_000169.3:c.1102G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_000169.3(GLA):​c.1102G>C​(p.Ala368Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,208,470 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A368T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000047 (0 hom. 14 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: -0.928
• Publications: 15 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 21 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21133766).
• BP6: Variant X-101397997-C-G is Benign according to our data. Variant chrX-101397997-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379288.
• BS2: High Hemizygotes in GnomAd4 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.1102G>C	p.Ala368Pro	missense	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1225G>C	p.Ala409Pro	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2540C>G		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.1102G>C	p.Ala368Pro	missense	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2540C>G		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1225G>C	p.Ala409Pro	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111925 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: 0.0000940

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183423 AF XY: 0.0000295

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: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 51 AN: 1096545 Hom.: 0 Cov.: 30 AF XY: 0.0000387 AC XY: 14 AN XY: 361935

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000535 AC: 45 AN: 840603

Other (OTH) AF: 0.000130 AC: 6 AN: 46031

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111925 Hom.: 0 Cov.: 23 AF XY: 0.0000586 AC XY: 2 AN XY: 34115

African (AFR) AF: 0.00 AC: 0 AN: 30752

American (AMR) AF: 0.00 AC: 0 AN: 10545

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53216

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Fabry disease (4)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
CardioboostCm	Benign	0.012
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.035
DANN	Benign	0.84
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	1.6	D
MutationAssessor	Benign	0.34	N
PhyloP100		-0.93
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.26
Sift	Benign	0.079	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.53		Loss of catalytic residue at A368 (P = 0.1111)
MVP		0.46
MPC		0.91
ClinPred		0.032	T
GERP RS		-8.2
Varity_R		0.43
gMVP		0.85
Mutation Taster		=92/8	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: rs144994244; hg19: chrX-100652985;