7-81720892-A-G

Variant names:

• chr7-81720892-A-G
• rs12536657
• NM_000601.6:c.1169-45T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000601.6(HGF):​c.1169-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 993,120 control chromosomes in the GnomAD database, including 335,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55678 hom., cov: 33)
  • Exomes 𝑓: 0.81 (279751 hom.)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• Publications: 20 publications found

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

ENSG00000300407 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 7-81720892-A-G is Benign according to our data. Variant chr7-81720892-A-G is described in ClinVar as Benign. ClinVar VariationId is 1246790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1169-45T>C		intron_variant	Intron 9 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1154-45T>C		intron_variant	Intron 9 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1169-45T>C		intron_variant	Intron 9 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129635 AN: 152116 Hom.: 55624 Cov.: 33

Gnomad AFR AF: 0.955

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.851

GnomAD2 exomes AF: 0.835 AC: 201034 AN: 240720 AF XY: 0.833

Gnomad AFR exome AF: 0.956

Gnomad AMR exome AF: 0.891

Gnomad ASJ exome AF: 0.868

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.824

GnomAD4 exome AF: 0.814 AC: 684405 AN: 840886 Hom.: 279751 Cov.: 11 AF XY: 0.815 AC XY: 361818 AN XY: 443766

African (AFR) AF: 0.957 AC: 20413 AN: 21330

American (AMR) AF: 0.889 AC: 38504 AN: 43292

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 19240 AN: 22188

East Asian (EAS) AF: 0.881 AC: 32380 AN: 36754

South Asian (SAS) AF: 0.865 AC: 63352 AN: 73210

European-Finnish (FIN) AF: 0.791 AC: 41687 AN: 52704

Middle Eastern (MID) AF: 0.867 AC: 3683 AN: 4250

European-Non Finnish (NFE) AF: 0.790 AC: 432294 AN: 547336

Other (OTH) AF: 0.825 AC: 32852 AN: 39822

GnomAD4 genome AF: 0.852 AC: 129748 AN: 152234 Hom.: 55678 Cov.: 33 AF XY: 0.852 AC XY: 63369 AN XY: 74414

African (AFR) AF: 0.955 AC: 39670 AN: 41560

American (AMR) AF: 0.870 AC: 13312 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2998 AN: 3470

East Asian (EAS) AF: 0.856 AC: 4435 AN: 5182

South Asian (SAS) AF: 0.873 AC: 4215 AN: 4826

European-Finnish (FIN) AF: 0.780 AC: 8251 AN: 10580

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.796 AC: 54134 AN: 68002

Other (OTH) AF: 0.849 AC: 1794 AN: 2112

Alfa AF: 0.820 Hom.: 7037

Bravo AF: 0.862

Asia WGS AF: 0.857 AC: 2982 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.046
DANN	Benign	0.32
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12536657; hg19: chr7-81350208;