7-81726029-A-G

Variant names:

• chr7-81726029-A-G
• rs546227025
• NM_000601.6:c.1041-12T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000601.6(HGF):​c.1041-12T>C variant causes a intron change. The variant allele was found at a frequency of 0.00015 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: HGF NM_000601.6 intron
• Scores: Splicing: ADA: 0.01080
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.23
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-81726029-A-G is Benign according to our data. Variant chr7-81726029-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	NM_000601.6	MANE Select	c.1041-12T>C		intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.1026-12T>C		intron	N/A	NP_001010932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.1041-12T>C		intron	N/A	ENSP00000222390.5
	HGF	ENST00000457544.7	TSL:1	c.1026-12T>C		intron	N/A	ENSP00000391238.2
	ENSG00000300407	ENST00000771413.1		n.117+25501A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251420 AF XY: 0.000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727062

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00254 AC: 219 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111648

Other (OTH) AF: 0.000199 AC: 12 AN: 60388

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		5.2
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.070		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: rs546227025; hg19: chr7-81355345;