chr7-81745064-A-C

Position:

• chr7-81745064-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000601.6(HGF):​c.682T>G​(p.Ser228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,962 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.43

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 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=0.13233131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6	c.682T>G	p.Ser228Ala	missense_variant	6/18	ENST00000222390.11	NP_000592.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.682T>G	p.Ser228Ala	missense_variant	6/18	1	NM_000601.6	ENSP00000222390	P4
HGF	ENST00000457544.7	c.667T>G	p.Ser223Ala	missense_variant	6/18	1		ENSP00000391238	A1
HGF	ENST00000444829.7	c.682T>G	p.Ser228Ala	missense_variant	6/8	1		ENSP00000389854
HGF	ENST00000453411.6	c.667T>G	p.Ser223Ala	missense_variant	6/8	1		ENSP00000408270

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251238 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000157

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 163662). This variant has not been reported in the literature in individuals affected with HGF-related conditions. This variant is present in population databases (rs139457161, gnomAD 0.03%). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 228 of the HGF protein (p.Ser228Ala). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31453292) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 17, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ser228Ala varia nt in HGF has not been reported in the literature nor previously identified by o ur laboratory. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ser228Ala variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been identified in 0.01% (1/8600) of Europea n American chromosomes in a broad population by the NHLBI Exome sequencing proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs139457161). Although this variant has been seen in the general population, its frequency is not high enough to ru le out a pathogenic role. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon computational analyses a nd presence in the general population in the absence of any data to support path ogenicity, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	.;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	.;N;N;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	.;D;D;D;D
Sift4G	Uncertain	0.0070	.;D;D;D;D
Polyphen		0.0020	B;B;B;B;B
Vest4		0.31, 0.31, 0.36, 0.36
MVP		0.76
MPC		0.49
ClinPred		0.25	T
GERP RS		2.2
Varity_R		0.55
gMVP		0.69

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: rs139457161; hg19: chr7-81374380;