chrX-84469203-T-C

Position:

• chrX-84469203-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001177479.2(HDX):​c.520A>G​(p.Ile174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

HDX (HGNC:26411): (highly divergent homeobox) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20866543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDX	NM_001177479.2	c.520A>G	p.Ile174Val	missense_variant	4/11	ENST00000373177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDX	ENST00000373177.3	c.520A>G	p.Ile174Val	missense_variant	4/11	1	NM_001177479.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182521 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67079

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

May 31, 2023

The c.520A>G (p.I174V) alteration is located in exon 4 (coding exon 2) of the HDX gene. This alteration results from a A to G substitution at nucleotide position 520, causing the isoleucine (I) at amino acid position 174 to be replaced by a valine (V). 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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.;T;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	.;T;T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	0.59	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.16	N;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.20	T;.;.;T
Sift4G	Benign	0.60	T;T;T;D
Polyphen		0.91	P;.;P;.
Vest4		0.20
MutPred		0.40		Loss of ubiquitination at K172 (P = 0.1306);.;Loss of ubiquitination at K172 (P = 0.1306);.;
MVP		0.38
MPC		0.38
ClinPred		0.32	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.18

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: rs1176539096; hg19: chrX-83724211;