7-81710234-A-G

Position:

• chr7-81710234-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000222390.11(HGF):​c.1454T>C​(p.Ile485Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HGF ENST00000222390.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2171998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6	c.1454T>C	p.Ile485Thr	missense_variant	13/18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1439T>C	p.Ile480Thr	missense_variant	13/18		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1454T>C	p.Ile485Thr	missense_variant	13/18	1	NM_000601.6	ENSP00000222390	P4
HGF	ENST00000457544.7	c.1439T>C	p.Ile480Thr	missense_variant	13/18	1		ENSP00000391238	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459034 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ile485Thr varia nt in HGF has not been reported in the literature or in large population studies , nor previously identified by our laboratory. The Ile485 residue is not highly conserved across species and computational analyses (biochemical amino acid prop erties, homology, PolyPhen2, AlignGVGD) do not provide strong support for pathog enicity. In summary, the clinical significance of this variant cannot be determi ned at this time; however, based upon lack of conservation, we would lean toward s a more likely benign interpretation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.28	.;T;T
Sift4G	Benign	0.24	.;T;T
Polyphen		0.061	B;B;B
Vest4		0.54, 0.54
MutPred		0.41		Gain of disorder (P = 0.1039);Gain of disorder (P = 0.1039);.;
MVP		0.70
MPC		0.79
ClinPred		0.47	T
GERP RS		5.2
Varity_R		0.41
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516446; hg19: chr7-81339550;