rs2887069

Variant names:

• chr7-81725750-G-A
• rs2887069
• NM_000601.6:c.1168+140C>T

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.1168+140C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 939,402 control chromosomes in the GnomAD database, including 311,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50010 hom., cov: 32)
  • Exomes 𝑓: 0.81 (261838 hom.)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0170
• Publications: 5 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=-0.89).
• BP6: Variant 7-81725750-G-A is Benign according to our data. Variant chr7-81725750-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1168+140C>T		intron_variant	Intron 9 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1153+140C>T		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.1168+140C>T		intron_variant	Intron 9 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123164 AN: 152000 Hom.: 49967 Cov.: 32

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.868

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.815

GnomAD4 exome AF: 0.815 AC: 641417 AN: 787284 Hom.: 261838 AF XY: 0.816 AC XY: 340395 AN XY: 417026

African (AFR) AF: 0.805 AC: 16532 AN: 20528

American (AMR) AF: 0.878 AC: 37623 AN: 42860

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 18627 AN: 21188

East Asian (EAS) AF: 0.882 AC: 32208 AN: 36526

South Asian (SAS) AF: 0.862 AC: 61101 AN: 70916

European-Finnish (FIN) AF: 0.812 AC: 39529 AN: 48704

Middle Eastern (MID) AF: 0.854 AC: 3735 AN: 4372

European-Non Finnish (NFE) AF: 0.795 AC: 400834 AN: 503930

Other (OTH) AF: 0.816 AC: 31228 AN: 38260

GnomAD4 genome AF: 0.810 AC: 123266 AN: 152118 Hom.: 50010 Cov.: 32 AF XY: 0.812 AC XY: 60342 AN XY: 74342

African (AFR) AF: 0.810 AC: 33599 AN: 41504

American (AMR) AF: 0.845 AC: 12910 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3037 AN: 3472

East Asian (EAS) AF: 0.853 AC: 4412 AN: 5170

South Asian (SAS) AF: 0.868 AC: 4179 AN: 4816

European-Finnish (FIN) AF: 0.802 AC: 8474 AN: 10568

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54034 AN: 67996

Other (OTH) AF: 0.814 AC: 1719 AN: 2112

Alfa AF: 0.808 Hom.: 24276

Bravo AF: 0.812

Asia WGS AF: 0.850 AC: 2956 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

- -

Mar 29, 2019

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	-0.89
CADD	Benign	0.66
DANN	Benign	0.26
PhyloP100		-0.017
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2887069; hg19: chr7-81355066;