Variant X-84333840-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001177479.2(HDX):c.1743A>C(p.Lys581Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000199 in 854,840 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 1 hem. )

Consequence

HDX
NM_001177479.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30330992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDX	NM_001177479.2 linkuse as main transcript	c.1743A>C	p.Lys581Asn	missense_variant, splice_region_variant	9/11	ENST00000373177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDX	ENST00000373177.3 linkuse as main transcript	c.1743A>C	p.Lys581Asn	missense_variant, splice_region_variant	9/11	1	NM_001177479.2	P1	Q7Z353-1
HDX	ENST00000297977.9 linkuse as main transcript	c.1743A>C	p.Lys581Asn	missense_variant, splice_region_variant	8/10	1		P1	Q7Z353-1
HDX	ENST00000506585.6 linkuse as main transcript	c.1569A>C	p.Lys523Asn	missense_variant, splice_region_variant	8/10	2			Q7Z353-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111440

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33754

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000961

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000450

AC:

AN:

133291

Hom.:

AF XY:

0.00

AC XY:

AN XY:

33745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000245

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:

0.00

Gnomad OTH exome

AF:

0.000301

GnomAD4 exome

AF:

0.0000202

AC:

AN:

743347

Hom.:

Cov.:

AF XY:

0.00000532

AC XY:

AN XY:

187913

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000234

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:

0.0000112

Gnomad4 OTH exome

AF:

0.0000597

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111493

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33817

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000960

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.1743A>C (p.K581N) alteration is located in exon 9 (coding exon 7) of the HDX gene. This alteration results from a A to C substitution at nucleotide position 1743, causing the lysine (K) at amino acid position 581 to be replaced by an asparagine (N). 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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

2.0

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.4

N;.;.

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.58

MutPred

0.28

Loss of ubiquitination at K581 (P = 0.0067);.;Loss of ubiquitination at K581 (P = 0.0067);

MVP

0.46

MPC

0.37

ClinPred

0.26

GERP RS

4.8

Varity_R

0.85

gMVP

0.35

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