4-3443112-G-C

Position:

• chr4-3443112-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001528.4(HGFAC):​c.361G>C​(p.Ala121Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HGFAC NM_001528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.21

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]

ACMG classification

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=0.32080317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4	c.361G>C	p.Ala121Pro	missense_variant	3/14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2	c.361G>C	p.Ala121Pro	missense_variant	3/15		NP_001284368.1
HGFAC	XM_047450155.1	c.10G>C	p.Ala4Pro	missense_variant	3/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8	c.361G>C	p.Ala121Pro	missense_variant	3/14	1	NM_001528.4	ENSP00000372224.4
HGFAC	ENST00000511533.1	c.361G>C	p.Ala121Pro	missense_variant	3/15	1		ENSP00000421801.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

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

Jun 28, 2024

The c.361G>C (p.A121P) alteration is located in exon 3 (coding exon 3) of the HGFAC gene. This alteration results from a G to C substitution at nucleotide position 361, causing the alanine (A) at amino acid position 121 to be replaced by a proline (P). 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	0.36
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.11
DANN	Benign	0.88
DEOGEN2	Benign	0.032	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.088
Sift	Benign	0.20	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.30	B;P
Vest4		0.16
MutPred		0.73		Gain of catalytic residue at A121 (P = 0.0189);Gain of catalytic residue at A121 (P = 0.0189);
MVP		0.099
MPC		0.22
ClinPred		0.25	T
GERP RS		-6.3
Varity_R		0.073
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3444839;