Genetic Variant HLF:p.Ala180Gly (chr17-55315314-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_002126.5(HLF):c.539C>G(p.Ala180Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HLF
NM_002126.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

Variant links:

Genes affected

HLF (HGNC:4977): (HLF transcription factor, PAR bZIP family member) This gene encodes a member of the proline and acidic-rich (PAR) protein family, a subset of the bZIP transcription factors. The encoded protein forms homodimers or heterodimers with other PAR family members and binds sequence-specific promoter elements to activate transcription. Chromosomal translocations fusing portions of this gene with the E2A gene cause a subset of childhood B-lineage acute lymphoid leukemias. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

HLF links:

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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=0.3320291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLF	NM_002126.5 link	c.539C>G	p.Ala180Gly	missense_variant	Exon 3 of 4	ENST00000226067.10	NP_002117.1	Q16534-1
HLF	NM_001330375.2 link	c.284C>G	p.Ala95Gly	missense_variant	Exon 3 of 4		NP_001317304.1	Q16534-2
HLF	XM_005257269.3 link	c.539C>G	p.Ala180Gly	missense_variant	Exon 3 of 4		XP_005257326.1
HLF	XM_047435895.1 link	c.284C>G	p.Ala95Gly	missense_variant	Exon 4 of 5		XP_047291851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLF	ENST00000226067.10 link	c.539C>G	p.Ala180Gly	missense_variant	Exon 3 of 4	1	NM_002126.5	ENSP00000226067.5		Q16534-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251364

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539C>G (p.A180G) alteration is located in exon 3 (coding exon 3) of the HLF gene. This alteration results from a C to G substitution at nucleotide position 539, causing the alanine (A) at amino acid position 180 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;.;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;.;.;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.8

M;.;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

D;D;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.049

D;T;.;.;.

Sift4G

Uncertain

0.059

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.39

MutPred

0.31

Gain of relative solvent accessibility (P = 0.0082);.;.;.;.;

MVP

0.20

MPC

1.7

ClinPred

0.92

GERP RS

5.6

Varity_R

0.47

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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