Genetic Variant HDX:p.Arg445Gln (chrX-84361584-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001177479.2(HDX):c.1334G>A(p.Arg445Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,199,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 9 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.482

Publications

0 publications found

Variant links:

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]

HDX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1090588).

BP6

Variant X-84361584-C-T is Benign according to our data. Variant chrX-84361584-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2399446.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 9 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDX	NM_001177479.2	MANE Select	c.1334G>A	p.Arg445Gln	missense	Exon 6 of 11	NP_001170950.1	Q7Z353-1
HDX	NM_144657.5		c.1334G>A	p.Arg445Gln	missense	Exon 5 of 10	NP_653258.2
HDX	NM_001177478.2		c.1160G>A	p.Arg387Gln	missense	Exon 5 of 10	NP_001170949.1	Q7Z353-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDX	ENST00000373177.3	TSL:1 MANE Select	c.1334G>A	p.Arg445Gln	missense	Exon 6 of 11	ENSP00000362272.2	Q7Z353-1
HDX	ENST00000297977.9	TSL:1	c.1334G>A	p.Arg445Gln	missense	Exon 5 of 10	ENSP00000297977.5	Q7Z353-1
HDX	ENST00000851225.1		c.1334G>A	p.Arg445Gln	missense	Exon 6 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

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:

0.00000577

AC:

AN:

173289

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000796

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:

0.0000175

AC:

AN:

1087603

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

353917

show subpopulations

African (AFR)

AF:

0.0000764

AC:

AN:

26169

American (AMR)

AF:

0.00

AC:

AN:

34639

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19177

East Asian (EAS)

AF:

0.00

AC:

AN:

29983

South Asian (SAS)

AF:

0.0000574

AC:

AN:

52227

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4107

European-Non Finnish (NFE)

AF:

0.0000132

AC:

AN:

835378

Other (OTH)

AF:

0.0000657

AC:

AN:

45673

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111698

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33888

show subpopulations

African (AFR)

AF:

0.0000651

AC:

AN:

30731

American (AMR)

AF:

0.00

AC:

AN:

10402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3585

South Asian (SAS)

AF:

0.00

AC:

AN:

2685

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6063

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53161

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.81

M_CAP

Benign

0.035

MetaRNN

Benign

0.11

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.55

PhyloP100

0.48

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.90

REVEL

Benign

0.20

Sift

Benign

0.098

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.16

MVP

0.55

MPC

0.14

ClinPred

0.12

GERP RS

1.5

Varity_R

0.095

gMVP

0.19

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over