chr4-3443348-A-C

Position:

• chr4-3443348-A-C

Variant summary

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

The NM_001528.4(HGFAC):​c.403A>C​(p.Thr135Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HGFAC NM_001528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.609

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=0.40385568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4	c.403A>C	p.Thr135Pro	missense_variant	4/14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2	c.403A>C	p.Thr135Pro	missense_variant	4/15		NP_001284368.1
HGFAC	XM_047450155.1	c.52A>C	p.Thr18Pro	missense_variant	4/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8	c.403A>C	p.Thr135Pro	missense_variant	4/14	1	NM_001528.4	ENSP00000372224.4
HGFAC	ENST00000511533.1	c.403A>C	p.Thr135Pro	missense_variant	4/15	1		ENSP00000421801.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jul 16, 2024

The c.403A>C (p.T135P) alteration is located in exon 4 (coding exon 4) of the HGFAC gene. This alteration results from a A to C substitution at nucleotide position 403, causing the threonine (T) at amino acid position 135 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	0.40
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.0070	B;B
Vest4		0.42
MutPred		0.82		Loss of glycosylation at T135 (P = 0.0472);Loss of glycosylation at T135 (P = 0.0472);
MVP		0.47
MPC		0.31
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.71
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs925474974; hg19: chr4-3445075;