rs374484762

Variant names:

• chr7-81729662-C-A
• rs374484762
• NM_000601.6:c.983G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-81729662-C-A
• chr7-81729662-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.14
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 39

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300407 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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	c.983G>T	p.Arg328Leu	missense_variant	Exon 8 of 18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.968G>T	p.Arg323Leu	missense_variant	Exon 8 of 18		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.983G>T	p.Arg328Leu	missense_variant	Exon 8 of 18	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.968G>T	p.Arg323Leu	missense_variant	Exon 8 of 18	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+29134C>A		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.172-7319C>A		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Uncertain	2.9	M;M;.
PhyloP100		5.1
PrimateAI	Uncertain	0.53	T
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	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.90
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs374484762; hg19: chr7-81358978; COSMIC: COSV55959117;