X-84321944-T-A

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

9
8

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]

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 UniProt
HDXNM_001177479.2 linkuse as main transcriptc.2018A>T p.Asp673Val missense_variant 11/11 ENST00000373177.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HDXENST00000373177.3 linkuse as main transcriptc.2018A>T p.Asp673Val missense_variant 11/111 NM_001177479.2 P1Q7Z353-1
HDXENST00000297977.9 linkuse as main transcriptc.2018A>T p.Asp673Val missense_variant 10/101 P1Q7Z353-1
HDXENST00000506585.6 linkuse as main transcriptc.1844A>T p.Asp615Val missense_variant 10/102 Q7Z353-2

Frequencies

GnomAD3 genomes
AF:
0.0000360
AC:
4
AN:
111046
Hom.:
0
Cov.:
22
AF XY:
0.0000298
AC XY:
1
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:
4
AN:
174470
Hom.:
0
AF XY:
0.0000166
AC XY:
1
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:
41
AN:
1066315
Hom.:
0
Cov.:
22
AF XY:
0.0000448
AC XY:
15
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:
4
AN:
111098
Hom.:
0
Cov.:
22
AF XY:
0.0000298
AC XY:
1
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:
1

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 submitterclinical testingAmbry GeneticsSep 14, 2023The 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
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T;.;T
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.79
.;T;T
M_CAP
Uncertain
0.25
D
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
2.0
M;.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.64
T
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
D
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.

Other links and lift over

dbSNP: rs779771605; hg19: chrX-83576952; API