Variant 1-220882257-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_021958.4(HLX):c.866A>C(p.Lys289Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLX
NM_021958.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

HLX (HGNC:4978): (H2.0 like homeobox) Enables sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; enteric nervous system development; and regulation of T-helper cell differentiation. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

HLX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLX	NM_021958.4 linkuse as main transcript	c.866A>C	p.Lys289Thr	missense_variant	3/4	ENST00000366903.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HLX	ENST00000366903.8 linkuse as main transcript	c.866A>C	p.Lys289Thr	missense_variant	3/4	1	NM_021958.4	P1
HLX	ENST00000427693.1 linkuse as main transcript	c.65A>C	p.Lys22Thr	missense_variant	3/4	3
HLX	ENST00000549319.2 linkuse as main transcript	n.2827A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151354

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000381

AC:

AN:

1445128

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

719556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000103

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000230

Gnomad4 NFE exome

AF:

0.0000327

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000594

AC:

AN:

151478

Hom.:

Cov.:

AF XY:

0.0000945

AC XY:

AN XY:

74052

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.866A>C (p.K289T) alteration is located in exon 3 (coding exon 3) of the HLX gene. This alteration results from a A to C substitution at nucleotide position 866, causing the lysine (K) at amino acid position 289 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

HLX-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

The HLX c.866A>C variant is predicted to result in the amino acid substitution p.Lys289Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-221055599-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.62

Sift

Benign

0.034

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.24

B;.

Vest4

0.80

MVP

0.97

MPC

1.4

ClinPred

0.97

GERP RS

6.1

Varity_R

0.46

gMVP

0.86

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