X-84344255-G-A

Position:

• chrX-84344255-G-A

Variant summary

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

The NM_001177479.2(HDX):​c.1655C>T​(p.Ser552Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000925 in 1,080,613 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.11

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDX	NM_001177479.2	c.1655C>T	p.Ser552Phe	missense_variant	7/11	ENST00000373177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDX	ENST00000373177.3	c.1655C>T	p.Ser552Phe	missense_variant	7/11	1	NM_001177479.2	P1
HDX	ENST00000297977.9	c.1655C>T	p.Ser552Phe	missense_variant	6/10	1		P1
HDX	ENST00000506585.6	c.1481C>T	p.Ser494Phe	missense_variant	6/10	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.25e-7 AC: 1 AN: 1080613 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 348269

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: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

Jul 05, 2022

The c.1655C>T (p.S552F) alteration is located in exon 7 (coding exon 5) of the HDX gene. This alteration results from a C to T substitution at nucleotide position 1655, causing the serine (S) at amino acid position 552 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.69
MutPred		0.15		Loss of phosphorylation at S552 (P = 0.0222);.;Loss of phosphorylation at S552 (P = 0.0222);
MVP		0.37
MPC		0.54
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-83599263;