dbSNP rs145598174: HGF:p.Asp90Glu (chr7-81758789-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000601.6(HGF):c.270T>G(p.Asp90Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,706 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D90D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HGF
NM_000601.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.667

Publications

0 publications found

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]

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

HGF links:

ENSG00000300407 (HGNC:):

ENSG00000300407 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.270T>G	p.Asp90Glu	missense_variant	Exon 3 of 18	ENST00000222390.11	NP_000592.3	P14210-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11 link	c.270T>G	p.Asp90Glu	missense_variant	Exon 3 of 18	1	NM_000601.6	ENSP00000222390.5		P14210-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458706

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725912

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109492

Other (OTH)

AF:

0.00

AC:

AN:

60276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.62

D;D;.;.;.;.;.;D;D;.;D

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

.;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.2

M;M;M;M;M;M;.;.;.;.;.

PhyloP100

0.67

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

.;N;N;N;N;N;.;N;.;N;D

REVEL

Uncertain

0.49

Sift

Benign

0.31

.;T;T;T;T;T;.;T;.;D;D

Sift4G

Benign

0.46

.;T;T;T;T;T;.;D;.;.;.

Polyphen

1.0

D;D;D;D;D;.;.;.;.;.;.

Vest4

0.23, 0.21, 0.21, 0.21, 0.21, 0.20

MutPred

0.75

Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);

MVP

0.84

MPC

0.47

ClinPred

0.69

GERP RS

-2.6

Varity_R

0.65

gMVP

0.73

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over