X-101411979-A-G

Position:

• chrX-101411979-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001199973.2(RPL36A-HNRNPH2):​c.344A>G​(p.Gln115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,075,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: RPL36A-HNRNPH2 NM_001199973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0897018).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPH2	NM_019597.5	c.-10A>G		5_prime_UTR_variant	2/2	ENST00000316594.6	NP_062543.1
RPL36A-HNRNPH2	NM_001199973.2	c.344A>G	p.Gln115Arg	missense_variant	5/5		NP_001186902.2
RPL36A-HNRNPH2	NM_001199974.2	c.221A>G	p.Gln74Arg	missense_variant	4/4		NP_001186903.2
HNRNPH2	NM_001032393.3	c.-10A>G		5_prime_UTR_variant	2/2		NP_001027565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL36A-HNRNPH2	ENST00000409170.3	c.344A>G	p.Gln115Arg	missense_variant	5/5	4		ENSP00000386655.4
HNRNPH2	ENST00000316594	c.-10A>G		5_prime_UTR_variant	2/2	1	NM_019597.5	ENSP00000361927.2
RPL36A-HNRNPH2	ENST00000409338.5	c.221A>G	p.Gln74Arg	missense_variant	4/4	4		ENSP00000386974.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000112 AC: 12 AN: 1075982 Hom.: 0 Cov.: 33 AF XY: 0.0000114 AC XY: 4 AN XY: 349470

Gnomad4 AFR exome AF: 0.000198

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000111

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

The c.452A>G (p.Q151R) alteration is located in exon 5 (coding exon 5) of the RPL36A-HNRNPH2 gene. This alteration results from a A to G substitution at nucleotide position 452, causing the glutamine (Q) at amino acid position 151 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.4
DANN	Benign	0.95
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.33	T
REVEL	Benign	0.061
Sift4G	Benign	0.31	T;.
Vest4		0.24
MVP		0.19
ClinPred		0.19	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs1928826688; hg19: chrX-100666967;