NM_002126.5:c.448C>A

Variant names:

• chr17-55268083-C-A
• rs977072851
• NM_002126.5:c.448C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002126.5(HLF):​c.448C>A​(p.Pro150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,390,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P150A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: HLF NM_002126.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13670558).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLF	NM_002126.5	MANE Select	c.448C>A	p.Pro150Thr	missense	Exon 2 of 4	NP_002117.1	Q16534-1
	HLF	NM_001330375.2		c.193C>A	p.Pro65Thr	missense	Exon 2 of 4	NP_001317304.1	Q16534-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLF	ENST00000226067.10	TSL:1 MANE Select	c.448C>A	p.Pro150Thr	missense	Exon 2 of 4	ENSP00000226067.5	Q16534-1
	HLF	ENST00000572002.1	TSL:3	c.268C>A	p.Pro90Thr	missense	Exon 1 of 3	ENSP00000461455.1	I3L4R4
	HLF	ENST00000430986.6	TSL:2	c.193C>A	p.Pro65Thr	missense	Exon 2 of 4	ENSP00000402496.2	Q16534-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390842 Hom.: 0 Cov.: 29 AF XY: 0.00000292 AC XY: 2 AN XY: 684504

African (AFR) AF: 0.00 AC: 0 AN: 31210

American (AMR) AF: 0.00 AC: 0 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21412

East Asian (EAS) AF: 0.00 AC: 0 AN: 38740

South Asian (SAS) AF: 0.00 AC: 0 AN: 74422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076594

Other (OTH) AF: 0.0000175 AC: 1 AN: 57256

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.78
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.13
Sift	Benign	0.48	T
Sift4G	Benign	0.16	T
Polyphen		0.049	B
Vest4		0.40
MutPred		0.13		Loss of relative solvent accessibility (P = 0.0306)
MVP		0.082
MPC		0.85
ClinPred		0.45	T
GERP RS		5.9
PromoterAI		0.0096	Neutral
Varity_R		0.14
gMVP		0.47
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs977072851; hg19: chr17-53345444;