Variant X-84321944-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001177479.2(HDX):c.2018A>T(p.Asp673Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000382 in 1,177,413 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000038 ( 0 hom. 15 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

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 -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDX	NM_001177479.2 linkuse as main transcript	c.2018A>T	p.Asp673Val	missense_variant	11/11	ENST00000373177.3	NP_001170950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDX	ENST00000373177.3 linkuse as main transcript	c.2018A>T	p.Asp673Val	missense_variant	11/11	1	NM_001177479.2	ENSP00000362272	P1	Q7Z353-1
HDX	ENST00000297977.9 linkuse as main transcript	c.2018A>T	p.Asp673Val	missense_variant	10/10	1		ENSP00000297977	P1	Q7Z353-1
HDX	ENST00000506585.6 linkuse as main transcript	c.1844A>T	p.Asp615Val	missense_variant	10/10	2		ENSP00000423670		Q7Z353-2

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

111046

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33526

show subpopulations

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:

0.0000762

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000229

AC:

AN:

174470

Hom.:

AF XY:

0.0000166

AC XY:

AN XY:

60374

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000384

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1066315

Hom.:

Cov.:

AF XY:

0.0000448

AC XY:

AN XY:

335193

show subpopulations

Gnomad4 AFR exome

AF:

0.0000390

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:

0.0000454

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000360

AC:

AN:

111098

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33588

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000762

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.2018A>T (p.D673V) alteration is located in exon 11 (coding exon 9) of the HDX gene. This alteration results from a A to T substitution at nucleotide position 2018, causing the aspartic acid (D) at amino acid position 673 to be replaced by a valine (V). 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

0.15

BayesDel_addAF

Benign

0.0065

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

.;T;T

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

2.0

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.5

D;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.016

D;.;.

Sift4G

Uncertain

0.057

T;T;T

Polyphen

1.0

D;.;D

Vest4

0.53

MVP

0.64

MPC

0.69

ClinPred

0.59

GERP RS

5.5

Varity_R

0.59

gMVP

0.25

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