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_000169.3(GLA):​c.1000-22C>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_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.1000-22C>T		intron_variant	Intron 6 of 6	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1000-22C>T		intron_variant	Intron 6 of 6	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2664G>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

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

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jul 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.1000-22C>T is located at a position not widely known to affect splicing. The variant allele was found at a frequency of 0.24 in 181209 control chromosomes in the gnomAD database, including 5568 homozygotes. The observed variant frequency is approximately 48.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLA causing Fabry Disease phenotype (0.005), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1000-22C>T in individuals affected with Fabry Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fabry disease Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;