Variant 1-220880393-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021958.4(HLX):c.536A>G(p.Asp179Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HLX
NM_021958.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.82

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:

ENSG00000286231 (HGNC:):

ENSG00000286231 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLX	NM_021958.4 linkuse as main transcript	c.536A>G	p.Asp179Gly	missense_variant	1/4	ENST00000366903.8	NP_068777.1	Q14774

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HLX	ENST00000366903.8 linkuse as main transcript	c.536A>G	p.Asp179Gly	missense_variant	1/4	1	NM_021958.4	ENSP00000355870.5	Q14774
ENSG00000286231	ENST00000651706.1 linkuse as main transcript	n.843-801A>G		intron_variant				ENSP00000499157.1	A0A494C1P3
HLX	ENST00000549319.2 linkuse as main transcript	n.963A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

244376

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

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:

0.00000274

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

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 30, 2024

The c.536A>G (p.D179G) alteration is located in exon 1 (coding exon 1) of the HLX gene. This alteration results from a A to G substitution at nucleotide position 536, causing the aspartic acid (D) at amino acid position 179 to be replaced by a glycine (G). 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

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.0

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.71

MutPred

0.32

Gain of catalytic residue at I178 (P = 0.1275);

MVP

0.77

MPC

1.5

ClinPred

0.95

GERP RS

4.7

Varity_R

0.62

gMVP

0.75

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