NM_000169.3:c.1102G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000169.3(GLA):​c.1102G>A​(p.Ala368Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,208,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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. A368P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 7 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• 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: Benign. The variant received -10 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=0.03427121).
• BP6: Variant X-101397997-C-T is Benign according to our data. Variant chrX-101397997-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42451.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000295 (33/111981) while in subpopulation AFR AF = 0.00107 (33/30821). AF 95% confidence interval is 0.000784. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 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>A	p.Ala368Thr	missense	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1225G>A	p.Ala409Thr	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2540C>T		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>A	p.Ala368Thr	missense	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2540C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1225G>A	p.Ala409Thr	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.000295 AC: 33 AN: 111925 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00107

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: 0.0000654 AC: 12 AN: 183423 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000912

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1096543 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 361935

African (AFR) AF: 0.000910 AC: 24 AN: 26360

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: 0.00 AC: 0 AN: 840603

Other (OTH) AF: 0.0000434 AC: 2 AN: 46031

GnomAD4 genome AF: 0.000295 AC: 33 AN: 111981 Hom.: 0 Cov.: 23 AF XY: 0.000234 AC XY: 8 AN XY: 34181

African (AFR) AF: 0.00107 AC: 33 AN: 30821

American (AMR) AF: 0.00 AC: 0 AN: 10558

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53209

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Fabry disease (5)
-	2	1	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostCm	Benign	0.0055
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0080
DANN	Benign	0.66
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.034	T
MetaSVM	Pathogenic	1.9	D
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.93
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.058
MVP		0.40
MPC		0.68
ClinPred		0.014	T
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.43
Mutation Taster		=91/9	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;