X-101411951-A-T

Variant names:

• chrX-101411951-A-T
• rs782687084
• ENST00000409170.3:c.316A>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001199973.2(RPL36A-HNRNPH2):​c.316A>T​(p.Ile106Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,030,489 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000039 (0 hom. 3 hem.)
• Consequence: RPL36A-HNRNPH2 NM_001199973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.312

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056492984).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPH2	NM_019597.5	c.-38A>T		5_prime_UTR_variant	Exon 2 of 2	ENST00000316594.6	NP_062543.1
RPL36A-HNRNPH2	NM_001199973.2	c.316A>T	p.Ile106Phe	missense_variant	Exon 5 of 5		NP_001186902.2
RPL36A-HNRNPH2	NM_001199974.2	c.193A>T	p.Ile65Phe	missense_variant	Exon 4 of 4		NP_001186903.2
HNRNPH2	NM_001032393.3	c.-38A>T		5_prime_UTR_variant	Exon 2 of 2		NP_001027565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL36A-HNRNPH2	ENST00000409170.3	c.316A>T	p.Ile106Phe	missense_variant	Exon 5 of 5	4		ENSP00000386655.4
HNRNPH2	ENST00000316594	c.-38A>T		5_prime_UTR_variant	Exon 2 of 2	1	NM_019597.5	ENSP00000361927.2
RPL36A-HNRNPH2	ENST00000409338.5	c.193A>T	p.Ile65Phe	missense_variant	Exon 4 of 4	4		ENSP00000386974.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000731 AC: 1 AN: 136790 Hom.: 0 AF XY: 0.0000229 AC XY: 1 AN XY: 43712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000907

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000388 AC: 4 AN: 1030489 Hom.: 0 Cov.: 33 AF XY: 0.00000919 AC XY: 3 AN XY: 326605

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000229

Gnomad4 FIN exome AF: 0.0000259

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000467

GnomAD4 genome Cov.: 21

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.424A>T (p.I142F) alteration is located in exon 5 (coding exon 5) of the RPL36A-HNRNPH2 gene. This alteration results from a A to T substitution at nucleotide position 424, causing the isoleucine (I) at amino acid position 142 to be replaced by a phenylalanine (F). 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	-0.55	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.54
DANN	Benign	0.67
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.27	T
REVEL	Benign	0.066
Sift4G	Uncertain	0.014	D;.
Vest4		0.26
MVP		0.15
ClinPred		0.032	T
GERP RS		-6.0
gMVP		0.034

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: rs782687084; hg19: chrX-100666939;