rs151195362

Variant names:

• chrX-101398391-C-T
• rs151195362
• NM_000169.3:c.978G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000169.3(GLA):​c.978G>A​(p.Lys326Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,204,535 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 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 0.00091 (0 hom., 32 hem., cov: 23)
  • Exomes 𝑓: 0.000096 (0 hom. 28 hem.)
• Consequence: GLA NM_000169.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.23
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-101398391-C-T is Benign according to our data. Variant chrX-101398391-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000905 (101/111571) while in subpopulation AFR AF = 0.00316 (97/30744). AF 95% confidence interval is 0.00265. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 32 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.978G>A	p.Lys326Lys	synonymous	Exon 6 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1101G>A	p.Lys367Lys	synonymous	Exon 7 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.978G>A	p.Lys326Lys	synonymous	Exon 6 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.978G>A	p.Lys326Lys	synonymous	Exon 6 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2934C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1101G>A	p.Lys367Lys	synonymous	Exon 7 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.000897 AC: 100 AN: 111518 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000287

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: 0.00

Gnomad OTH AF: 0.000671

GnomAD2 exomes AF: 0.000267 AC: 49 AN: 183470 AF XY: 0.000280

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000961 AC: 105 AN: 1092964 Hom.: 0 Cov.: 30 AF XY: 0.0000781 AC XY: 28 AN XY: 358726

African (AFR) AF: 0.00247 AC: 65 AN: 26290

American (AMR) AF: 0.000568 AC: 20 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4098

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837358

Other (OTH) AF: 0.000370 AC: 17 AN: 45925

GnomAD4 genome AF: 0.000905 AC: 101 AN: 111571 Hom.: 0 Cov.: 23 AF XY: 0.000948 AC XY: 32 AN XY: 33755

African (AFR) AF: 0.00316 AC: 97 AN: 30744

American (AMR) AF: 0.000286 AC: 3 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5969

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53134

Other (OTH) AF: 0.000662 AC: 1 AN: 1510

Alfa AF: 0.000773 Hom.: 10

Bravo AF: 0.00120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	4	Fabry disease (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.9
DANN	Benign	0.79
PhyloP100		1.2
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: rs151195362; hg19: chrX-100653379;