rs2071225

Variant names:

• chrX-101407913-G-A
• rs2071225
• NM_000169.3:c.-10C>T

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.-10C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 1,201,243 control chromosomes in the GnomAD database, including 2,804 homozygotes. There are 31,097 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (208 hom., 2527 hem., cov: 23)
  • Exomes 𝑓: 0.074 (2596 hom. 28570 hem.)
• Consequence: GLA NM_000169.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -0.554
• Publications: 47 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]

HNRNPH2 (HGNC:5042): (heterogeneous nuclear ribonucleoprotein H2) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that binds to RNAs. It is very similar to the family member HNRPH1. This gene is thought to be involved in Fabray disease and X-linked agammaglobulinemia phenotype. Alternative splicing results in multiple transcript variants encoding the same protein. Read-through transcription between this locus and the ribosomal protein L36a gene has been observed. [provided by RefSeq, Jan 2011]

HNRNPH2 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked, syndromic, Bain type

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-101407913-G-A is Benign according to our data. Variant chrX-101407913-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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.-10C>T		5_prime_UTR	Exon 1 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.-10C>T		5_prime_UTR	Exon 1 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.-10C>T		5_prime_UTR	Exon 1 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.-10C>T		5_prime_UTR	Exon 1 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4023G>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000710365.1		c.-10C>T		5_prime_UTR	Exon 1 of 8	ENSP00000518234.1	A0AA34QW02

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 7839 AN: 111984 Hom.: 209 Cov.: 23

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.0968

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0793

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0462

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0677

GnomAD2 exomes AF: 0.0932 AC: 17056 AN: 182908 AF XY: 0.0995

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0510

Gnomad EAS exome AF: 0.0768

Gnomad FIN exome AF: 0.0633

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0736 AC: 80193 AN: 1089205 Hom.: 2596 Cov.: 31 AF XY: 0.0804 AC XY: 28570 AN XY: 355297

African (AFR) AF: 0.0712 AC: 1866 AN: 26202

American (AMR) AF: 0.111 AC: 3887 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 998 AN: 19338

East Asian (EAS) AF: 0.0781 AC: 2357 AN: 30168

South Asian (SAS) AF: 0.266 AC: 14333 AN: 53865

European-Finnish (FIN) AF: 0.0645 AC: 2611 AN: 40510

Middle Eastern (MID) AF: 0.0643 AC: 246 AN: 3827

European-Non Finnish (NFE) AF: 0.0603 AC: 50301 AN: 834373

Other (OTH) AF: 0.0785 AC: 3594 AN: 45761

GnomAD4 genome AF: 0.0699 AC: 7833 AN: 112038 Hom.: 208 Cov.: 23 AF XY: 0.0738 AC XY: 2527 AN XY: 34230

African (AFR) AF: 0.0670 AC: 2064 AN: 30804

American (AMR) AF: 0.0731 AC: 777 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 143 AN: 2654

East Asian (EAS) AF: 0.0792 AC: 281 AN: 3547

South Asian (SAS) AF: 0.278 AC: 747 AN: 2689

European-Finnish (FIN) AF: 0.0641 AC: 391 AN: 6096

Middle Eastern (MID) AF: 0.0461 AC: 10 AN: 217

European-Non Finnish (NFE) AF: 0.0611 AC: 3250 AN: 53188

Other (OTH) AF: 0.0682 AC: 104 AN: 1525

Alfa AF: 0.0632 Hom.: 646

Bravo AF: 0.0696

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Fabry disease (6)
-	-	6	not provided (6)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.3
DANN	Benign	0.79
PhyloP100		-0.55
PromoterAI		-0.23	Neutral
Mutation Taster		=298/2	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: rs2071225; hg19: chrX-100662901; COSMIC: COSV54509325; COSMIC: COSV54509325;