rs372600489

Positions:

• chr7-81745087-C-A
• chr7-81745087-C-G
• chr7-81745087-C-T

Variant summary

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

The NM_000601.6(HGF):​c.659G>T​(p.Arg220Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R220Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.96

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGF	NM_000601.6	c.659G>T	p.Arg220Leu	missense_variant	6/18	ENST00000222390.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGF	ENST00000222390.11	c.659G>T	p.Arg220Leu	missense_variant	6/18	1	NM_000601.6	P4
HGF	ENST00000457544.7	c.644G>T	p.Arg215Leu	missense_variant	6/18	1		A1
HGF	ENST00000444829.7	c.659G>T	p.Arg220Leu	missense_variant	6/8	1
HGF	ENST00000453411.6	c.644G>T	p.Arg215Leu	missense_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.7	H;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.1	.;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0070	.;D;D;D;D
Polyphen		0.36	B;B;B;D;B
Vest4		0.86, 0.88, 0.90, 0.90
MutPred		0.74		Loss of disorder (P = 0.0416);Loss of disorder (P = 0.0416);.;Loss of disorder (P = 0.0416);.;
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.91

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: chr7-81374403;