rs3748034

Variant names:

• chr4-3444364-G-A
• NM_001528.4:c.652G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3444364-G-A
• chr4-3444364-G-T

Variant summary

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

The NM_001528.4(HGFAC):​c.652G>A​(p.Ala218Thr) 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. 13/21 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. A218S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HGFAC NM_001528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23667279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGFAC	NM_001528.4	c.652G>A	p.Ala218Thr	missense_variant	Exon 6 of 14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2	c.652G>A	p.Ala218Thr	missense_variant	Exon 6 of 15		NP_001284368.1
HGFAC	XM_047450155.1	c.301G>A	p.Ala101Thr	missense_variant	Exon 6 of 14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8	c.652G>A	p.Ala218Thr	missense_variant	Exon 6 of 14	1	NM_001528.4	ENSP00000372224.4
HGFAC	ENST00000511533.1	c.652G>A	p.Ala218Thr	missense_variant	Exon 6 of 15	1		ENSP00000421801.1
HGFAC	ENST00000509689.5	n.16G>A		non_coding_transcript_exon_variant	Exon 1 of 9	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448268 Hom.: 0 Cov.: 54 AF XY: 0.00 AC XY: 0 AN XY: 719272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.042
Sift	Benign	0.39	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.42	B;D
Vest4		0.37
MutPred		0.29		Gain of phosphorylation at A218 (P = 0.0189);Gain of phosphorylation at A218 (P = 0.0189);
MVP		0.22
MPC		0.25
ClinPred		0.91	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3446091;