chr7-81729637-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_000601.6(HGF):​c.1008G>A​(p.Glu336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,613,782 control chromosomes in the GnomAD database, including 9 homozygotes. 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 0.0019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0029 ( 8 hom. )

Consequence

HGF
NM_000601.6 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.509
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
Variant 7-81729637-C-T is Benign according to our data. Variant chr7-81729637-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr7-81729637-C-T is described in Lovd as [Benign]. Variant chr7-81729637-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.509 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HGFNM_000601.6 linkuse as main transcriptc.1008G>A p.Glu336= synonymous_variant 8/18 ENST00000222390.11
HGFNM_001010932.3 linkuse as main transcriptc.993G>A p.Glu331= synonymous_variant 8/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HGFENST00000222390.11 linkuse as main transcriptc.1008G>A p.Glu336= synonymous_variant 8/181 NM_000601.6 P4P14210-1
HGFENST00000457544.7 linkuse as main transcriptc.993G>A p.Glu331= synonymous_variant 8/181 A1P14210-3

Frequencies

GnomAD3 genomes
AF:
0.00192
AC:
292
AN:
152094
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000459
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00413
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00298
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00170
AC:
428
AN:
251444
Hom.:
1
AF XY:
0.00155
AC XY:
210
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00228
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000370
Gnomad NFE exome
AF:
0.00273
Gnomad OTH exome
AF:
0.00407
GnomAD4 exome
AF:
0.00286
AC:
4187
AN:
1461570
Hom.:
8
Cov.:
31
AF XY:
0.00278
AC XY:
2018
AN XY:
727112
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00253
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.000356
Gnomad4 NFE exome
AF:
0.00347
Gnomad4 OTH exome
AF:
0.00286
GnomAD4 genome
AF:
0.00192
AC:
292
AN:
152212
Hom.:
1
Cov.:
32
AF XY:
0.00177
AC XY:
132
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.00412
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00298
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00230
Hom.:
0
Bravo
AF:
0.00220
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00256
EpiControl
AF:
0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023HGF: BP4, BP7 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 09, 2017- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 25, 2023- -
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 27, 2020- -
not specified Benign:2
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Glu336Glu in Exon 08 of HGF: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 0.3% (24/7020) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs148714837). -
Autosomal recessive nonsyndromic hearing loss 39 Benign:1
Likely benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterJun 28, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Benign
5.5
DANN
Benign
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs148714837; hg19: chr7-81358953; API