chr4-3444364-G-T

Variant names:

• chr4-3444364-G-T
• rs3748034
• NM_001528.4:c.652G>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.652G>T​(p.Ala218Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,600,170 control chromosomes in the GnomAD database, including 18,346 homozygotes. 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: 𝑓 0.12 (1439 hom., cov: 34)
  • Exomes 𝑓: 0.14 (16907 hom.)
• Consequence: HGFAC NM_001528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 38 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=0.0068543255).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGFAC	NM_001528.4	c.652G>T	p.Ala218Ser	missense_variant	Exon 6 of 14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2	c.652G>T	p.Ala218Ser	missense_variant	Exon 6 of 15		NP_001284368.1
HGFAC	XM_047450155.1	c.301G>T	p.Ala101Ser	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>T	p.Ala218Ser	missense_variant	Exon 6 of 14	1	NM_001528.4	ENSP00000372224.4
HGFAC	ENST00000511533.1	c.652G>T	p.Ala218Ser	missense_variant	Exon 6 of 15	1		ENSP00000421801.1
HGFAC	ENST00000509689.5	n.16G>T		non_coding_transcript_exon_variant	Exon 1 of 9	5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17852 AN: 152016 Hom.: 1436 Cov.: 34

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.151 AC: 33210 AN: 219790 AF XY: 0.149

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.145 AC: 209333 AN: 1448036 Hom.: 16907 Cov.: 54 AF XY: 0.145 AC XY: 104002 AN XY: 719146

African (AFR) AF: 0.0305 AC: 1017 AN: 33382

American (AMR) AF: 0.175 AC: 7466 AN: 42574

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3168 AN: 25762

East Asian (EAS) AF: 0.327 AC: 12766 AN: 39068

South Asian (SAS) AF: 0.133 AC: 11169 AN: 84084

European-Finnish (FIN) AF: 0.124 AC: 6296 AN: 50926

Middle Eastern (MID) AF: 0.109 AC: 623 AN: 5732

European-Non Finnish (NFE) AF: 0.143 AC: 158630 AN: 1106646

Other (OTH) AF: 0.137 AC: 8198 AN: 59862

GnomAD4 genome AF: 0.117 AC: 17853 AN: 152134 Hom.: 1439 Cov.: 34 AF XY: 0.119 AC XY: 8842 AN XY: 74368

African (AFR) AF: 0.0365 AC: 1516 AN: 41550

American (AMR) AF: 0.138 AC: 2115 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1547 AN: 5158

South Asian (SAS) AF: 0.137 AC: 662 AN: 4816

European-Finnish (FIN) AF: 0.129 AC: 1373 AN: 10618

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9857 AN: 67904

Other (OTH) AF: 0.117 AC: 247 AN: 2110

Alfa AF: 0.137 Hom.: 3722

Bravo AF: 0.116

TwinsUK AF: 0.157 AC: 581

ALSPAC AF: 0.145 AC: 558

ESP6500AA AF: 0.0345 AC: 150

ESP6500EA AF: 0.140 AC: 1203

ExAC AF: 0.139 AC: 16653

Asia WGS AF: 0.188 AC: 654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		2.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.058
Sift	Benign	0.40	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.42	B;P
Vest4		0.13
MPC		0.19
ClinPred		0.015	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3748034; hg19: chr4-3446091; COSMIC: COSV58751226; COSMIC: COSV58751226;