4-3444041-GCCCTGGATCCCTGTGC-G

Position:

• chr4-3444041-GCCCTGGATCCCTGTGC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001528.4(HGFAC):​c.480_495delCCTGGATCCCTGTGCC​(p.Leu161fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,596,092 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (26 hom.)
• Consequence: HGFAC NM_001528.4 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.15

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 4-3444041-GCCCTGGATCCCTGTGC-G is Benign according to our data. Variant chr4-3444041-GCCCTGGATCCCTGTGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 2654603.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00237 (3422/1443848) while in subpopulation MID AF= 0.0232 (131/5648). AF 95% confidence interval is 0.02. There are 26 homozygotes in gnomad4_exome. There are 1998 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4	c.480_495delCCTGGATCCCTGTGCC	p.Leu161fs	frameshift_variant	5/14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2	c.480_495delCCTGGATCCCTGTGCC	p.Leu161fs	frameshift_variant	5/15		NP_001284368.1
HGFAC	XM_047450155.1	c.129_144delCCTGGATCCCTGTGCC	p.Leu44fs	frameshift_variant	5/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8	c.480_495delCCTGGATCCCTGTGCC	p.Leu161fs	frameshift_variant	5/14	1	NM_001528.4	ENSP00000372224.4
HGFAC	ENST00000511533.1	c.480_495delCCTGGATCCCTGTGCC	p.Leu161fs	frameshift_variant	5/15	1		ENSP00000421801.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152128 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00257 AC: 599 AN: 232910 Hom.: 2 AF XY: 0.00306 AC XY: 388 AN XY: 126880

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00237 AC: 3422 AN: 1443848 Hom.: 26 AF XY: 0.00278 AC XY: 1998 AN XY: 717878

Gnomad4 AFR exome AF: 0.000307

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.00826

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00857

Gnomad4 FIN exome AF: 0.00393

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00423

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152244 Hom.: 3 Cov.: 34 AF XY: 0.00265 AC XY: 197 AN XY: 74438

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00482 Hom.: 1

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

HGFAC: BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs562047823; hg19: chr4-3445768;