NM_000601.6:c.2011-78C>A

Variant names:

• chr7-81702835-G-T
• rs5745766
• NM_000601.6:c.2011-78C>A

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.2011-78C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,173,910 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (132 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (92 hom.)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.116
• Publications: 0 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: G2P, Ambry Genetics, 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=-0.81).
• BP6: Variant 7-81702835-G-T is Benign according to our data. Variant chr7-81702835-G-T is described in ClinVar as Benign. ClinVar VariationId is 1244067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000601.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	NM_000601.6	MANE Select	c.2011-78C>A		intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.1996-78C>A		intron	N/A	NP_001010932.1	P14210-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.2011-78C>A		intron	N/A	ENSP00000222390.5	P14210-1
	HGF	ENST00000457544.7	TSL:1	c.1996-78C>A		intron	N/A	ENSP00000391238.2	P14210-3
	ENSG00000300407	ENST00000771413.1		n.117+2307G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3502 AN: 151512 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.0202

GnomAD4 exome AF: 0.00250 AC: 2558 AN: 1022280 Hom.: 92 AF XY: 0.00211 AC XY: 1113 AN XY: 526958

African (AFR) AF: 0.0824 AC: 1917 AN: 23266

American (AMR) AF: 0.00523 AC: 218 AN: 41698

Ashkenazi Jewish (ASJ) AF: 0.0000879 AC: 2 AN: 22760

East Asian (EAS) AF: 0.00 AC: 0 AN: 35404

South Asian (SAS) AF: 0.0000678 AC: 5 AN: 73742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51694

Middle Eastern (MID) AF: 0.00367 AC: 18 AN: 4902

European-Non Finnish (NFE) AF: 0.000174 AC: 126 AN: 723348

Other (OTH) AF: 0.00598 AC: 272 AN: 45466

GnomAD4 genome AF: 0.0231 AC: 3499 AN: 151630 Hom.: 132 Cov.: 32 AF XY: 0.0221 AC XY: 1636 AN XY: 74110

African (AFR) AF: 0.0785 AC: 3254 AN: 41452

American (AMR) AF: 0.0121 AC: 183 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67710

Other (OTH) AF: 0.0200 AC: 42 AN: 2102

Alfa AF: 0.00660 Hom.: 17

Bravo AF: 0.0266

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		-0.12
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: rs5745766; hg19: chr7-81332151;