rs727503071

Variant names:

• chrX-101400675-G-A
• rs727503071
• NM_000169.3:c.630C>T
• GLA p.Pro210Pro

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_ModerateBP7

The NM_000169.3(GLA):c.630C>T (p.Pro210Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.237
• 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]

GLA Gene-Disease associations (from GenCC):

• Fabry disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen

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]

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -5 points.

• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
• BP7: Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.630C>T	p.Pro210Pro	synonymous	Exon 4 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.753C>T	p.Pro251Pro	synonymous	Exon 5 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.630C>T	p.Pro210Pro	synonymous	Exon 4 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.630C>T	p.Pro210Pro	synonymous	Exon 4 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+5218G>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.753C>T	p.Pro251Pro	synonymous	Exon 5 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.2
DANN	Benign	0.52
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727503071;

hg19: chrX-100655663;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar