Genetic Variant HDX:p.Pro561Leu (chrX-84336859-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001177479.2(HDX):c.1682C>T(p.Pro561Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,180,010 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 8 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073681).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDX	NM_001177479.2 link	c.1682C>T	p.Pro561Leu	missense_variant	Exon 8 of 11	ENST00000373177.3	NP_001170950.1	Q7Z353-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDX	ENST00000373177.3 link	c.1682C>T	p.Pro561Leu	missense_variant	Exon 8 of 11	1	NM_001177479.2	ENSP00000362272.2	Q7Z353-1
HDX	ENST00000297977.9 link	c.1682C>T	p.Pro561Leu	missense_variant	Exon 7 of 10	1		ENSP00000297977.5	Q7Z353-1
HDX	ENST00000506585.6 link	c.1508C>T	p.Pro503Leu	missense_variant	Exon 7 of 10	2		ENSP00000423670.2	Q7Z353-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

110598

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

33062

show subpopulations

Gnomad AFR

AF:

0.0000328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000388

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:

0.0000570

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000542

AC:

AN:

166112

Hom.:

AF XY:

0.0000751

AC XY:

AN XY:

53230

show subpopulations

Gnomad AFR exome

AF:

0.0000818

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000619

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000135

Gnomad OTH exome

AF:

0.000248

GnomAD4 exome

AF:

0.0000196

AC:

AN:

1069412

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

339030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000390

Gnomad4 AMR exome

AF:

0.000357

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000393

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000609

Gnomad4 OTH exome

AF:

0.0000222

GnomAD4 genome

AF:

0.0000723

AC:

AN:

110598

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

33062

show subpopulations

Gnomad4 AFR

AF:

0.0000328

Gnomad4 AMR

AF:

0.000388

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000570

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1682C>T (p.P561L) alteration is located in exon 8 (coding exon 6) of the HDX gene. This alteration results from a C to T substitution at nucleotide position 1682, causing the proline (P) at amino acid position 561 to be replaced by a leucine (L). 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

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.9

DANN

Benign

0.85

DEOGEN2

Benign

0.056

T;.;T

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.40

.;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.074

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.28

N;D;.

REVEL

Benign

0.034

Sift

Benign

0.22

T;D;.

Sift4G

Benign

0.33

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.078

MutPred

0.19

Loss of loop (P = 0.0128);.;Loss of loop (P = 0.0128);

MVP

0.082

MPC

0.12

ClinPred

0.33

GERP RS

4.5

Varity_R

0.035

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over