dbSNP rs374484762: HGF:p.Arg328Leu (chr7-81729662-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000601.6(HGF):c.983G>T(p.Arg328Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HGF
NM_000601.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 5.14

Variant links:

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]

HGF links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.983G>T	p.Arg328Leu	missense_variant	Exon 8 of 18	ENST00000222390.11	NP_000592.3	P14210-1
HGF	NM_001010932.3 link	c.968G>T	p.Arg323Leu	missense_variant	Exon 8 of 18		NP_001010932.1	P14210-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11 link	c.983G>T	p.Arg328Leu	missense_variant	Exon 8 of 18	1	NM_000601.6	ENSP00000222390.5		P14210-1
HGF	ENST00000457544.7 link	c.968G>T	p.Arg323Leu	missense_variant	Exon 8 of 18	1		ENSP00000391238.2		P14210-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg328Leu variant in HGF has not been previously reported in individuals wit h hearing loss, but has been identified in 0.01% (1/8600) of European American c hromosomes (http://evs.gs.washington.edu/EVS/). Although this variant has been s een in the general population, its frequency is not high enough to rule out a pa thogenic role. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or aga inst pathogenicity. In summary, additional information is needed to determine th e clinical significance of this variant. -

Autosomal recessive nonsyndromic hearing loss 39

Uncertain:1

Nov 12, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

-0.051

MutationAssessor

Uncertain

2.9

M;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.7

.;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

0.98

D;D;D

Vest4

0.72, 0.73

MutPred

0.67

Loss of disorder (P = 0.0897);Loss of disorder (P = 0.0897);.;

MVP

0.90

MPC

1.5

ClinPred

1.0

GERP RS

5.8

Varity_R

0.58

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over