rs2074725

Variant names:

• chr7-81709988-A-C
• rs2074725
• NM_000601.6:c.1541+159T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-81709988-A-C
• chr7-81709988-A-G
• chr7-81709988-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000601.6(HGF):​c.1541+159T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 152,014 control chromosomes in the GnomAD database, including 43,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.75 (43207 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113
• Publications: 12 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 7-81709988-A-C is Benign according to our data. Variant chr7-81709988-A-C is described in ClinVar as Benign. ClinVar VariationId is 1287559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1541+159T>G		intron_variant	Intron 13 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1526+159T>G		intron_variant	Intron 13 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1541+159T>G		intron_variant	Intron 13 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113516 AN: 151894 Hom.: 43183 Cov.: 32

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.778

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.747 AC: 113594 AN: 152014 Hom.: 43207 Cov.: 32 AF XY: 0.750 AC XY: 55703 AN XY: 74296

African (AFR) AF: 0.591 AC: 24485 AN: 41446

American (AMR) AF: 0.827 AC: 12611 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3018 AN: 3470

East Asian (EAS) AF: 0.858 AC: 4413 AN: 5146

South Asian (SAS) AF: 0.871 AC: 4198 AN: 4818

European-Finnish (FIN) AF: 0.781 AC: 8249 AN: 10566

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54051 AN: 67996

Other (OTH) AF: 0.777 AC: 1642 AN: 2114

Alfa AF: 0.786 Hom.: 75295

Bravo AF: 0.742

Asia WGS AF: 0.841 AC: 2923 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

- -

Nov 12, 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	-0.84
CADD	Benign	21
DANN	Benign	0.84
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2074725; hg19: chr7-81339304; COSMIC: COSV55952180;