7-81762824-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000601.6(HGF):​c.137C>T​(p.Ala46Val) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,596,858 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

HGF
NM_000601.6 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.49
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009344757).
BP6
Variant 7-81762824-G-A is Benign according to our data. Variant chr7-81762824-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360784.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr7-81762824-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HGFNM_000601.6 linkuse as main transcriptc.137C>T p.Ala46Val missense_variant 2/18 ENST00000222390.11 NP_000592.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HGFENST00000222390.11 linkuse as main transcriptc.137C>T p.Ala46Val missense_variant 2/181 NM_000601.6 ENSP00000222390 P4P14210-1

Frequencies

GnomAD3 genomes
AF:
0.00133
AC:
202
AN:
151986
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00177
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00113
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00207
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.00178
AC:
446
AN:
250740
Hom.:
0
AF XY:
0.00179
AC XY:
242
AN XY:
135536
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000638
Gnomad ASJ exome
AF:
0.00506
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00273
Gnomad NFE exome
AF:
0.00259
Gnomad OTH exome
AF:
0.000817
GnomAD4 exome
AF:
0.00182
AC:
2632
AN:
1444754
Hom.:
4
Cov.:
27
AF XY:
0.00176
AC XY:
1269
AN XY:
719900
show subpopulations
Gnomad4 AFR exome
AF:
0.000423
Gnomad4 AMR exome
AF:
0.000627
Gnomad4 ASJ exome
AF:
0.00542
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000489
Gnomad4 FIN exome
AF:
0.00238
Gnomad4 NFE exome
AF:
0.00200
Gnomad4 OTH exome
AF:
0.00144
GnomAD4 genome
AF:
0.00133
AC:
202
AN:
152104
Hom.:
0
Cov.:
32
AF XY:
0.00136
AC XY:
101
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00177
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00113
Gnomad4 NFE
AF:
0.00207
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.00221
Hom.:
0
Bravo
AF:
0.00139
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.00337
AC:
13
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00221
AC:
19
ExAC
AF:
0.00180
AC:
218
EpiCase
AF:
0.00185
EpiControl
AF:
0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 05, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 06, 2018This variant is associated with the following publications: (PMID: 29924831) -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The HGF p.Ala46Val variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs150267054), ClinVar (classified as a VUS by Illumina for Nonsyndromic Hearing Loss, Mixed and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS and likely benign). The variant was also identified in control databases in 482 of 282092 chromosomes at a frequency of 0.001709 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 53 of 10362 chromosomes (freq: 0.005115), European (Finnish) in 66 of 25094 chromosomes (freq: 0.00263), European (non-Finnish) in 320 of 128720 chromosomes (freq: 0.002486), Other in 5 of 7206 chromosomes (freq: 0.000694), Latino in 22 of 35338 chromosomes (freq: 0.000623), South Asian in 10 of 30548 chromosomes (freq: 0.000327) and African in 6 of 24922 chromosomes (freq: 0.000241) but was not observed in the East Asian population. The p.Ala46 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Nonsyndromic Hearing Loss, Mixed Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 30, 2016p.Ala46Val in exon 2 of HGF: This variant is not expected to have clinical signi ficance because it has been identified in 0.3% (196/64768) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs150267054). -
HGF-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 11, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;D;.;.;.;.;.;D;D;.;D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.0093
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.6
L;L;L;L;L;L;.;.;.;.;.
MutationTaster
Benign
0.98
D;D;D;D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.0
.;N;N;N;N;N;.;N;.;N;N
REVEL
Benign
0.12
Sift
Benign
0.17
.;T;T;T;T;T;.;T;.;T;D
Sift4G
Benign
0.29
.;T;T;T;T;T;.;D;.;.;.
Polyphen
0.96
D;D;P;P;P;.;.;.;.;.;.
Vest4
0.31, 0.33, 0.35, 0.35, 0.32, 0.32
MVP
0.64
MPC
1.1
ClinPred
0.019
T
GERP RS
5.9
Varity_R
0.76
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs150267054; hg19: chr7-81392140; API