Variant X-84468603-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001177479.2(HDX):c.1120A>G(p.Thr374Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,204,975 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

HDX
NM_001177479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039604843).

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDX	NM_001177479.2 linkuse as main transcript	c.1120A>G	p.Thr374Ala	missense_variant	4/11	ENST00000373177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDX	ENST00000373177.3 linkuse as main transcript	c.1120A>G	p.Thr374Ala	missense_variant	4/11	1	NM_001177479.2	P1	Q7Z353-1
HDX	ENST00000297977.9 linkuse as main transcript	c.1120A>G	p.Thr374Ala	missense_variant	3/10	1		P1	Q7Z353-1
HDX	ENST00000506585.6 linkuse as main transcript	c.946A>G	p.Thr316Ala	missense_variant	3/10	2			Q7Z353-2
HDX	ENST00000472135.2 linkuse as main transcript	n.974A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

112105

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34251

show subpopulations

Gnomad AFR

AF:

0.000422

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000283

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:

0.00

Gnomad OTH

AF:

0.000654

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183336

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67798

show subpopulations

Gnomad AFR exome

AF:

0.000380

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000915

AC:

AN:

1092817

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

358431

show subpopulations

Gnomad4 AFR exome

AF:

0.000267

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.000152

AC:

AN:

112158

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

34314

show subpopulations

Gnomad4 AFR

AF:

0.000421

Gnomad4 AMR

AF:

0.000283

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:

0.000646

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

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

Apr 22, 2022

The c.1120A>G (p.T374A) alteration is located in exon 4 (coding exon 2) of the HDX gene. This alteration results from a A to G substitution at nucleotide position 1120, causing the threonine (T) at amino acid position 374 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

Benign

0.072

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.95

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.044

T;.;T

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.66

.;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;.;N

MutationTaster

Benign

0.86

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.21

N;.;.

REVEL

Benign

0.079

Sift

Benign

0.25

T;.;.

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.14

MVP

0.13

MPC

0.12

ClinPred

0.029

GERP RS

2.8

Varity_R

0.035

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