4-3442075-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001528.4(HGFAC):c.74T>A(p.Leu25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,554,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
HGFAC
NM_001528.4 missense
NM_001528.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: -0.437
Genes affected
HGFAC (HGNC:4894): (HGF activator) This gene encodes a member of the peptidase S1 protein family. The encoded protein is first synthesized as an inactive single-chain precursor before being activated to a heterodimeric form by endoproteolytic processing. It acts as serine protease that converts hepatocyte growth factor to the active form. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
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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 |
---|---|---|---|---|---|---|---|---|
HGFAC | NM_001528.4 | c.74T>A | p.Leu25Gln | missense_variant | 1/14 | ENST00000382774.8 | NP_001519.1 | |
HGFAC | NM_001297439.2 | c.74T>A | p.Leu25Gln | missense_variant | 1/15 | NP_001284368.1 | ||
HGFAC | XM_047450155.1 | c.-235+256T>A | intron_variant | XP_047306111.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000525 AC: 1AN: 190362Hom.: 0 AF XY: 0.00000928 AC XY: 1AN XY: 107782
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GnomAD4 exome AF: 0.0000128 AC: 18AN: 1402480Hom.: 0 Cov.: 32 AF XY: 0.0000143 AC XY: 10AN XY: 697806
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74338
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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 | Aug 16, 2021 | The c.74T>A (p.L25Q) alteration is located in exon 1 (coding exon 1) of the HGFAC gene. This alteration results from a T to A substitution at nucleotide position 74, causing the leucine (L) at amino acid position 25 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of disorder (P = 0.0291);Gain of disorder (P = 0.0291);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at