Genetic Variant HDX:p.Cys430Phe (chrX-84440548-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001177479.2(HDX):c.1289G>T(p.Cys430Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000288 in 1,181,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 6 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.69

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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDX	NM_001177479.2 link	c.1289G>T	p.Cys430Phe	missense_variant	Exon 5 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.1289G>T	p.Cys430Phe	missense_variant	Exon 5 of 11	1	NM_001177479.2	ENSP00000362272.2	Q7Z353-1
HDX	ENST00000297977.9 link	c.1289G>T	p.Cys430Phe	missense_variant	Exon 4 of 10	1		ENSP00000297977.5	Q7Z353-1
HDX	ENST00000506585.6 link	c.1115G>T	p.Cys372Phe	missense_variant	Exon 4 of 10	2		ENSP00000423670.2	Q7Z353-2
HDX	ENST00000472135.2 link	n.1143G>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000990

AC:

AN:

111103

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33445

show subpopulations

Gnomad AFR

AF:

0.000131

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

175663

Hom.:

AF XY:

0.0000164

AC XY:

AN XY:

61111

show subpopulations

Gnomad AFR exome

AF:

0.0000791

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000253

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1070015

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

340685

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000257

Gnomad4 OTH exome

AF:

0.0000443

GnomAD4 genome

AF:

0.0000990

AC:

AN:

111103

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33445

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1289G>T (p.C430F) alteration is located in exon 5 (coding exon 3) of the HDX gene. This alteration results from a G to T substitution at nucleotide position 1289, causing the cysteine (C) at amino acid position 430 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

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;.;D

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;.;L

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.9

D;.;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

D;.;.

Sift4G

Uncertain

0.043

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.80

MVP

0.72

MPC

0.66

ClinPred

0.60

GERP RS

5.4

Varity_R

0.73

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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