NM_000169.3:c.714T>C

Variant names:

• chrX-101398872-A-G
• rs397515872
• NM_000169.3:c.714T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000169.3(GLA):​c.714T>C​(p.Ser238Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,206,302 control chromosomes in the GnomAD database, including 1 homozygotes. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (1 hom. 4 hem.)
• Consequence: GLA NM_000169.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.544
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-101398872-A-G is Benign according to our data. Variant chrX-101398872-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42460.
• BP7: Synonymous conserved (PhyloP=0.544 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.714T>C	p.Ser238Ser	synonymous	Exon 5 of 7	NP_000160.1
	GLA	NM_001406747.1		c.837T>C	p.Ser279Ser	synonymous	Exon 6 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.714T>C	p.Ser238Ser	synonymous	Exon 5 of 6	NP_001393677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.714T>C	p.Ser238Ser	synonymous	Exon 5 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3415A>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.837T>C	p.Ser279Ser	synonymous	Exon 6 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112330 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183483 AF XY: 0.0000294

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: 0.0000625

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1093972 Hom.: 1 Cov.: 30 AF XY: 0.0000111 AC XY: 4 AN XY: 359450

African (AFR) AF: 0.00 AC: 0 AN: 26322

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.00000954 AC: 8 AN: 838258

Other (OTH) AF: 0.000109 AC: 5 AN: 45947

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112330 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34480

African (AFR) AF: 0.0000324 AC: 1 AN: 30880

American (AMR) AF: 0.000189 AC: 2 AN: 10587

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6155

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53300

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.2
DANN	Benign	0.69
PhyloP100		0.54
Mutation Taster		=100/0	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: rs397515872; hg19: chrX-100653860;