rs2071228

Variant names:

• chrX-101398121-G-A
• rs2071228
• NM_000169.3:c.1000-22C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101398121-G-A
• chrX-101398121-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001406747.1(GLA):​c.1123-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,194,299 control chromosomes in the GnomAD database, including 24,964 homozygotes. There are 78,455 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (7174 hom., 10814 hem., cov: 24)
  • Exomes 𝑓: 0.19 (17790 hom. 67641 hem.)
• Consequence: GLA NM_001406747.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.27
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-101398121-G-A is Benign according to our data. Variant chrX-101398121-G-A is described in ClinVar as Benign. ClinVar VariationId is 222112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

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.1000-22C>T		intron	N/A	NP_000160.1
	GLA	NM_001406747.1		c.1123-22C>T		intron	N/A	NP_001393676.1
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2664G>A		intron	N/A	NP_001186902.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1000-22C>T		intron	N/A	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2664G>A		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1123-22C>T		intron	N/A	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 36769 AN: 111857 Hom.: 7167 Cov.: 24

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.198

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.241 AC: 43681 AN: 181209 AF XY: 0.231

Gnomad AFR exome AF: 0.759

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.188 AC: 203964 AN: 1082383 Hom.: 17790 Cov.: 29 AF XY: 0.194 AC XY: 67641 AN XY: 349521

African (AFR) AF: 0.763 AC: 19923 AN: 26103

American (AMR) AF: 0.290 AC: 10190 AN: 35098

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 2769 AN: 19291

East Asian (EAS) AF: 0.130 AC: 3924 AN: 30134

South Asian (SAS) AF: 0.419 AC: 22528 AN: 53749

European-Finnish (FIN) AF: 0.103 AC: 4168 AN: 40516

Middle Eastern (MID) AF: 0.172 AC: 694 AN: 4038

European-Non Finnish (NFE) AF: 0.157 AC: 129779 AN: 827890

Other (OTH) AF: 0.219 AC: 9989 AN: 45564

GnomAD4 genome AF: 0.329 AC: 36826 AN: 111916 Hom.: 7174 Cov.: 24 AF XY: 0.317 AC XY: 10814 AN XY: 34106

African (AFR) AF: 0.748 AC: 22902 AN: 30629

American (AMR) AF: 0.244 AC: 2590 AN: 10634

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 370 AN: 2643

East Asian (EAS) AF: 0.128 AC: 455 AN: 3553

South Asian (SAS) AF: 0.429 AC: 1166 AN: 2717

European-Finnish (FIN) AF: 0.0976 AC: 597 AN: 6116

Middle Eastern (MID) AF: 0.207 AC: 45 AN: 217

European-Non Finnish (NFE) AF: 0.154 AC: 8202 AN: 53202

Other (OTH) AF: 0.279 AC: 426 AN: 1527

Alfa AF: 0.225 Hom.: 26626

Bravo AF: 0.358

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	14
DANN	Benign	0.61
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs2071228; hg19: chrX-100653109; COSMIC: COSV54508145; COSMIC: COSV54508145;