rs16844401

Variant names:

• chr4-3447925-G-A
• rs16844401
• NM_001528.4:c.1526G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3447925-G-A
• chr4-3447925-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001528.4(HGFAC):​c.1526G>A​(p.Arg509His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,609,362 control chromosomes in the GnomAD database, including 4,523 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.057 (367 hom., cov: 34)
  • Exomes 𝑓: 0.070 (4156 hom.)
• Consequence: HGFAC NM_001528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 56 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022737384).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001528.4. 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
	HGFAC	NM_001528.4	MANE Select	c.1526G>A	p.Arg509His	missense	Exon 12 of 14	NP_001519.1	Q04756
	HGFAC	NM_001297439.2		c.1547G>A	p.Arg516His	missense	Exon 13 of 15	NP_001284368.1	D6RAR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGFAC	ENST00000382774.8	TSL:1 MANE Select	c.1526G>A	p.Arg509His	missense	Exon 12 of 14	ENSP00000372224.4	Q04756
	HGFAC	ENST00000511533.1	TSL:1	c.1547G>A	p.Arg516His	missense	Exon 13 of 15	ENSP00000421801.1	D6RAR4
	HGFAC	ENST00000882393.1		c.1706G>A	p.Arg569His	missense	Exon 12 of 14	ENSP00000552452.1

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8754 AN: 152182 Hom.: 369 Cov.: 34

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0755

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0481

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0645

GnomAD2 exomes AF: 0.0747 AC: 18084 AN: 241986 AF XY: 0.0773

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.0849

Gnomad EAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0704

Gnomad OTH exome AF: 0.0831

GnomAD4 exome AF: 0.0698 AC: 101724 AN: 1457062 Hom.: 4156 Cov.: 33 AF XY: 0.0714 AC XY: 51727 AN XY: 724462

African (AFR) AF: 0.0265 AC: 884 AN: 33406

American (AMR) AF: 0.0730 AC: 3233 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 2214 AN: 26034

East Asian (EAS) AF: 0.121 AC: 4789 AN: 39540

South Asian (SAS) AF: 0.111 AC: 9505 AN: 85594

European-Finnish (FIN) AF: 0.0521 AC: 2698 AN: 51800

Middle Eastern (MID) AF: 0.114 AC: 652 AN: 5732

European-Non Finnish (NFE) AF: 0.0663 AC: 73596 AN: 1110380

Other (OTH) AF: 0.0689 AC: 4153 AN: 60258

GnomAD4 genome AF: 0.0574 AC: 8744 AN: 152300 Hom.: 367 Cov.: 34 AF XY: 0.0585 AC XY: 4359 AN XY: 74452

African (AFR) AF: 0.0277 AC: 1150 AN: 41572

American (AMR) AF: 0.0753 AC: 1152 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3472

East Asian (EAS) AF: 0.0914 AC: 473 AN: 5176

South Asian (SAS) AF: 0.110 AC: 531 AN: 4824

European-Finnish (FIN) AF: 0.0481 AC: 511 AN: 10624

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0653 AC: 4441 AN: 68020

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0662 Hom.: 1281

Bravo AF: 0.0588

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0706 AC: 272

ESP6500AA AF: 0.0280 AC: 123

ESP6500EA AF: 0.0683 AC: 587

ExAC AF: 0.0725 AC: 8766

Asia WGS AF: 0.0820 AC: 286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.26
Sift	Benign	0.20	T
Sift4G	Benign	0.64	T
Polyphen		0.10	B
Vest4		0.22
MPC		0.15
ClinPred		0.013	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.63
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16844401; hg19: chr4-3449652; COSMIC: COSV66977020;