chr7-81729735-C-G

Variant names:

• chr7-81729735-C-G
• rs5745687
• NM_000601.6:c.910G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000601.6(HGF):​c.910G>C​(p.Glu304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. E304K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22449979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.910G>C	p.Glu304Gln	missense_variant	Exon 8 of 18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.895G>C	p.Glu299Gln	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.910G>C	p.Glu304Gln	missense_variant	Exon 8 of 18	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.895G>C	p.Glu299Gln	missense_variant	Exon 8 of 18	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+29207C>G		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.172-7246C>G		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;.
Eigen	Benign	-0.028
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.33	.;N;N
REVEL	Benign	0.065
Sift	Benign	0.39	.;T;T
Sift4G	Benign	0.52	.;T;T
Polyphen		0.38	B;B;P
Vest4		0.25, 0.25
MutPred		0.32		Loss of disorder (P = 0.2133);Loss of disorder (P = 0.2133);.;
MVP		0.72
MPC		0.68
ClinPred		0.49	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.74
Mutation Taster		=100/0	polymorphism

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: rs5745687; hg19: chr7-81359051;