rs2074725

Positions:

• chr7-81709988-A-C
• chr7-81709988-A-G
• chr7-81709988-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000601.6(HGF):​c.1541+159T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 152,014 control chromosomes in the GnomAD database, including 43,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.75 (43207 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113

Genes affected

HGF (HGNC:4893): (hepatocyte growth factor) This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-81709988-A-C is Benign according to our data. Variant chr7-81709988-A-C is described in ClinVar as [Benign]. Clinvar id is 1287559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6	c.1541+159T>G		intron_variant		ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1526+159T>G		intron_variant			NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1541+159T>G		intron_variant		1	NM_000601.6	ENSP00000222390	P4
HGF	ENST00000457544.7	c.1526+159T>G		intron_variant		1		ENSP00000391238	A1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113516 AN: 151894 Hom.: 43183 Cov.: 32

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.778

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.747 AC: 113594 AN: 152014 Hom.: 43207 Cov.: 32 AF XY: 0.750 AC XY: 55703 AN XY: 74296

Gnomad4 AFR AF: 0.591

Gnomad4 AMR AF: 0.827

Gnomad4 ASJ AF: 0.870

Gnomad4 EAS AF: 0.858

Gnomad4 SAS AF: 0.871

Gnomad4 FIN AF: 0.781

Gnomad4 NFE AF: 0.795

Gnomad4 OTH AF: 0.777

Alfa AF: 0.793 Hom.: 59242

Bravo AF: 0.742

Asia WGS AF: 0.841 AC: 2923 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	21
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2074725; hg19: chr7-81339304; COSMIC: COSV55952180;