chrX-84468706-A-T

Variant names:

• chrX-84468706-A-T
• rs757035536
• NM_001177479.2:c.1017T>A

Variant summary

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

The NM_001177479.2(HDX):​c.1017T>A​(p.Ser339Arg) 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. 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: 1.34

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=0.17795596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDX	NM_001177479.2	c.1017T>A	p.Ser339Arg	missense_variant	Exon 4 of 11	ENST00000373177.3	NP_001170950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDX	ENST00000373177.3	c.1017T>A	p.Ser339Arg	missense_variant	Exon 4 of 11	1	NM_001177479.2	ENSP00000362272.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182687 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1017T>A (p.S339R) alteration is located in exon 4 (coding exon 2) of the HDX gene. This alteration results from a T to A substitution at nucleotide position 1017, causing the serine (S) at amino acid position 339 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
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;.;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;.;.
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.93	P;.;P
Vest4		0.44
MutPred		0.17		Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);
MVP		0.90
MPC		0.61
ClinPred		0.39	T
GERP RS		5.5
Varity_R		0.36
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs757035536; hg19: chrX-83723714;