X-101407933-C-T

Variant names:

• chrX-101407933-C-T
• rs3027584
• ENST00000409170.3:c.301-4003C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199973.2(RPL36A-HNRNPH2):​c.301-4003C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,149,952 control chromosomes in the GnomAD database, including 77 homozygotes. There are 4,453 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 0.0084 (2 hom., 236 hem., cov: 23)
  • Exomes 𝑓: 0.013 (75 hom. 4217 hem.)
• Consequence: RPL36A-HNRNPH2 NM_001199973.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.648
• Publications: 16 publications found

Genes affected

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]

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]

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=-0.56).
• BP6: Variant X-101407933-C-T is Benign according to our data. Variant chrX-101407933-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0132 (13732/1037831) while in subpopulation NFE AF = 0.0154 (12142/788041). AF 95% confidence interval is 0.0152. There are 75 homozygotes in GnomAdExome4. There are 4217 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199973.2. 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
	RPL36A-HNRNPH2	NM_001199973.2		c.301-4003C>T		intron	N/A	NP_001186902.2	H7BZ11
	RPL36A-HNRNPH2	NM_001199974.2		c.178-4003C>T		intron	N/A	NP_001186903.2	H0Y3V9
	GLA	NM_000169.3	MANE Select	c.-30G>A		upstream_gene	N/A	NP_000160.1	P06280

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4003C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	RPL36A-HNRNPH2	ENST00000409338.5	TSL:4	c.178-4003C>T		intron	N/A	ENSP00000386974.2	H0Y3V9
	GLA	ENST00000468823.2	TSL:5	n.32G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 945 AN: 112067 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00470

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00930

GnomAD2 exomes AF: 0.00863 AC: 1570 AN: 181938 AF XY: 0.00875

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.00994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0132 AC: 13732 AN: 1037831 Hom.: 75 Cov.: 27 AF XY: 0.0136 AC XY: 4217 AN XY: 310627

African (AFR) AF: 0.00171 AC: 43 AN: 25210

American (AMR) AF: 0.00230 AC: 81 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.00935 AC: 178 AN: 19028

East Asian (EAS) AF: 0.0000668 AC: 2 AN: 29942

South Asian (SAS) AF: 0.00454 AC: 238 AN: 52392

European-Finnish (FIN) AF: 0.0135 AC: 548 AN: 40494

Middle Eastern (MID) AF: 0.00259 AC: 9 AN: 3470

European-Non Finnish (NFE) AF: 0.0154 AC: 12142 AN: 788041

Other (OTH) AF: 0.0111 AC: 491 AN: 44104

GnomAD4 genome AF: 0.00842 AC: 944 AN: 112121 Hom.: 2 Cov.: 23 AF XY: 0.00688 AC XY: 236 AN XY: 34305

African (AFR) AF: 0.00152 AC: 47 AN: 30892

American (AMR) AF: 0.00470 AC: 50 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 27 AN: 2650

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

South Asian (SAS) AF: 0.00185 AC: 5 AN: 2702

European-Finnish (FIN) AF: 0.0105 AC: 64 AN: 6089

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0138 AC: 735 AN: 53161

Other (OTH) AF: 0.00918 AC: 14 AN: 1525

Alfa AF: 0.0101 Hom.: 149

Bravo AF: 0.00775

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Fabry disease (6)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.2
DANN	Benign	0.86
PhyloP100		-0.65
PromoterAI		0.054	Neutral

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: rs3027584; hg19: chrX-100662921; COSMIC: COSV54508869; COSMIC: COSV54508869;