7-81705509-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000601.6(HGF):c.1891G>A(p.Val631Met) variant causes a missense change. The variant allele was found at a frequency of 0.000716 in 1,612,546 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.20

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21294397).
• BP6: Variant 7-81705509-C-T is Benign according to our data. Variant chr7-81705509-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178380.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, Likely_benign=1}. Variant chr7-81705509-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGF	NM_000601.6	c.1891G>A	p.Val631Met	missense_variant	17/18	ENST00000222390.11
HGF	NM_001010932.3	c.1876G>A	p.Val626Met	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGF	ENST00000222390.11	c.1891G>A	p.Val631Met	missense_variant	17/18	1	NM_000601.6	P4
HGF	ENST00000457544.7	c.1876G>A	p.Val626Met	missense_variant	17/18	1		A1

Frequencies

GnomAD3 genomes AF: 0.000547 AC: 83 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000528

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000973

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000583 AC: 146 AN: 250462 Hom.: 0 AF XY: 0.000665 AC XY: 90 AN XY: 135366

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000733 AC: 1071 AN: 1460740 Hom.: 0 Cov.: 31 AF XY: 0.000750 AC XY: 545 AN XY: 726672

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000426

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: 0.000906

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000547 AC: 83 AN: 151806 Hom.: 0 Cov.: 32 AF XY: 0.000607 AC XY: 45 AN XY: 74174

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000527

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000973

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000946 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00147

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 631 of the HGF protein (p.Val631Met). This variant is present in population databases (rs145494248, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with HGF-related conditions (PMID: 18564920). ClinVar contains an entry for this variant (Variation ID: 178380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	This variant is associated with the following publications: (PMID: 18564920) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	HGF: PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 24, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Val631Met var iant in HGF has been previously reported by our laboratory in the heterozygous s tate in 3 individuals with hearing loss, none of whom has a second variant on th e other allele. This variant has been identified in 0.11% (132/125958) of Europe an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs145494248). Although this variant has been seen in the gen eral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Val631Met variant is uncertain; however, we would lean towards a benign role based on population frequency. ACMG/AMP Criteria applied: BS1_Suppo rting. -

Autosomal recessive nonsyndromic hearing loss 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
Polyphen		1.0	D;D;D
Vest4		0.78, 0.74
MVP		0.86
MPC		1.4
ClinPred		0.055	T
GERP RS		5.0
Varity_R		0.37
gMVP		0.65

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: rs145494248; hg19: chr7-81334825;