Variant X-84361503-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001177479.2(HDX):c.1415T>C(p.Val472Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,206,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 0 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.17

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3267101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDX	NM_001177479.2 linkuse as main transcript	c.1415T>C	p.Val472Ala	missense_variant	6/11	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.1415T>C	p.Val472Ala	missense_variant	6/11	1	NM_001177479.2	ENSP00000362272	P1	Q7Z353-1
HDX	ENST00000297977.9 linkuse as main transcript	c.1415T>C	p.Val472Ala	missense_variant	5/10	1		ENSP00000297977	P1	Q7Z353-1
HDX	ENST00000506585.6 linkuse as main transcript	c.1241T>C	p.Val414Ala	missense_variant	5/10	2		ENSP00000423670		Q7Z353-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34142

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000554

AC:

AN:

180613

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65281

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1094619

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360193

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:

0.00000596

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34142

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

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

May 06, 2022

The c.1415T>C (p.V472A) alteration is located in exon 6 (coding exon 4) of the HDX gene. This alteration results from a T to C substitution at nucleotide position 1415, causing the valine (V) at amino acid position 472 to be replaced by an alanine (A). 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

Uncertain

0.39

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;T

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

.;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

-0.23

N;.;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.63

N;.;.

REVEL

Uncertain

0.59

Sift

Benign

0.25

T;.;.

Sift4G

Benign

0.77

T;T;T

Polyphen

0.78

P;.;P

Vest4

0.29

MutPred

0.33

Loss of catalytic residue at V472 (P = 0.022);.;Loss of catalytic residue at V472 (P = 0.022);

MVP

0.73

MPC

0.26

ClinPred

0.90

GERP RS

5.4

Varity_R

0.14

gMVP

0.46

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