7-81705466-T-C

Position:

chr7-81705466-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000601.6(HGF):c.1934A>G(p.His645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,612,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

HGF
NM_000601.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13099405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6 linkuse as main transcript	c.1934A>G	p.His645Arg	missense_variant	17/18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3 linkuse as main transcript	c.1919A>G	p.His640Arg	missense_variant	17/18		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11 linkuse as main transcript	c.1934A>G	p.His645Arg	missense_variant	17/18	1	NM_000601.6	ENSP00000222390	P4	P14210-1
HGF	ENST00000457544.7 linkuse as main transcript	c.1919A>G	p.His640Arg	missense_variant	17/18	1		ENSP00000391238	A1	P14210-3

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250636

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1460844

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151938

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000395

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000366

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2024	The c.1934A>G (p.H645R) alteration is located in exon 17 (coding exon 17) of the HGF gene. This alteration results from a A to G substitution at nucleotide position 1934, causing the histidine (H) at amino acid position 645 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 25, 2017	The p.His645Arg variant in HGF has not been previously reported in individuals w ith hearing loss, but has been identified in 10/126034 European chromosomes and 3/34290 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs202215700). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analyses suggest tha t this variant may not impact the protein, though this information is not predic tive enough to rule out pathogenicity. In summary, the clinical significance of the p.His645Arg variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.62

D;D;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.84

.;T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

-0.55

N;N;.

MutationTaster

Benign

0.57

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

.;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.37

.;T;T

Sift4G

Benign

0.35

.;T;T

Polyphen

0.020

B;B;B

Vest4

0.30, 0.31

MVP

0.60

MPC

0.62

ClinPred

0.043

GERP RS

5.0

Varity_R

0.18

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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