chrX-84468634-A-T

Variant names:

• chrX-84468634-A-T
• rs774383837
• NM_001177479.2:c.1089T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001177479.2(HDX):​c.1089T>A​(p.Asn363Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,205,244 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14566308).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177479.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDX	NM_001177479.2	MANE Select	c.1089T>A	p.Asn363Lys	missense	Exon 4 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.1089T>A	p.Asn363Lys	missense	Exon 3 of 10	NP_653258.2
	HDX	NM_001177478.2		c.915T>A	p.Asn305Lys	missense	Exon 3 of 10	NP_001170949.1	Q7Z353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDX	ENST00000373177.3	TSL:1 MANE Select	c.1089T>A	p.Asn363Lys	missense	Exon 4 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.1089T>A	p.Asn363Lys	missense	Exon 3 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.1089T>A	p.Asn363Lys	missense	Exon 4 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111676 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 182983 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 9 AN: 1093568 Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 4 AN XY: 359032

African (AFR) AF: 0.000152 AC: 4 AN: 26307

American (AMR) AF: 0.00 AC: 0 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 54001

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4125

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837970

Other (OTH) AF: 0.0000218 AC: 1 AN: 45944

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111676 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33858

African (AFR) AF: 0.00 AC: 0 AN: 30699

American (AMR) AF: 0.00 AC: 0 AN: 10543

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53134

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.044
Sift	Uncertain	0.028	D
Sift4G	Benign	0.071	T
Polyphen		0.012	B
Vest4		0.50
MutPred		0.21		Gain of ubiquitination at N363 (P = 0.0138)
MVP		0.11
MPC		0.15
ClinPred		0.025	T
GERP RS		1.5
Varity_R		0.12
gMVP		0.31
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs774383837; hg19: chrX-83723642;