17-55315303-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002126.5(HLF):c.528G>C(p.Glu176Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0883773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLF	NM_002126.5	c.528G>C	p.Glu176Asp	missense_variant	3/4	ENST00000226067.10
HLF	NM_001330375.2	c.273G>C	p.Glu91Asp	missense_variant	3/4
HLF	XM_005257269.3	c.528G>C	p.Glu176Asp	missense_variant	3/4
HLF	XM_047435895.1	c.273G>C	p.Glu91Asp	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLF	ENST00000226067.10	c.528G>C	p.Glu176Asp	missense_variant	3/4	1	NM_002126.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.528G>C (p.E176D) alteration is located in exon 3 (coding exon 3) of the HLF gene. This alteration results from a G to C substitution at nucleotide position 528, causing the glutamic acid (E) at amino acid position 176 to be replaced by an aspartic acid (D). 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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.058	T;.;.;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;.;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.088	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.97	N;N;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.37	T;T;.;.;.
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.11
MutPred		0.23		Loss of sheet (P = 0.1501);.;.;.;.;
MVP		0.17
MPC		0.71
ClinPred		0.13	T
GERP RS		-2.2
Varity_R		0.13
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1222425771; hg19: chr17-53392664;