chr7-81758726-T-C

Variant names:

• chr7-81758726-T-C
• rs5745635
• NM_000601.6:c.333A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000601.6(HGF):​c.333A>G​(p.Glu111Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,612,428 control chromosomes in the GnomAD database, including 3,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1859 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1930 hom.)
• Consequence: HGF NM_000601.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.990
• Publications: 11 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 Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-81758726-T-C is Benign according to our data. Variant chr7-81758726-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 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.333A>G	p.Glu111Glu	synonymous	Exon 3 of 18	NP_000592.3
	HGF	NM_001010932.3		c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 18	NP_001010932.1	P14210-3
	HGF	NM_001010931.3		c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 8	NP_001010931.1	P14210-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 18	ENSP00000222390.5	P14210-1
	HGF	ENST00000457544.7	TSL:1	c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 18	ENSP00000391238.2	P14210-3
	HGF	ENST00000444829.7	TSL:1	c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 8	ENSP00000389854.2	P14210-2

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14017 AN: 152024 Hom.: 1854 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0414

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00963

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00861

Gnomad OTH AF: 0.0649

GnomAD2 exomes AF: 0.0362 AC: 9106 AN: 251234 AF XY: 0.0332

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.0224

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00925

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00851

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0193 AC: 28241 AN: 1460286 Hom.: 1930 Cov.: 29 AF XY: 0.0200 AC XY: 14504 AN XY: 726592

African (AFR) AF: 0.302 AC: 10084 AN: 33374

American (AMR) AF: 0.0244 AC: 1090 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00939 AC: 245 AN: 26104

East Asian (EAS) AF: 0.00733 AC: 290 AN: 39548

South Asian (SAS) AF: 0.0690 AC: 5949 AN: 86194

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53368

Middle Eastern (MID) AF: 0.0460 AC: 265 AN: 5758

European-Non Finnish (NFE) AF: 0.00741 AC: 8232 AN: 1110888

Other (OTH) AF: 0.0333 AC: 2010 AN: 60336

GnomAD4 genome AF: 0.0924 AC: 14058 AN: 152142 Hom.: 1859 Cov.: 32 AF XY: 0.0912 AC XY: 6783 AN XY: 74358

African (AFR) AF: 0.294 AC: 12218 AN: 41488

American (AMR) AF: 0.0413 AC: 632 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00965 AC: 50 AN: 5182

South Asian (SAS) AF: 0.0755 AC: 364 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.00861 AC: 585 AN: 67954

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0405 Hom.: 1822

Bravo AF: 0.103

Asia WGS AF: 0.0690 AC: 240 AN: 3470

EpiCase AF: 0.00987

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Nonsyndromic Hearing Loss, Mixed (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.48
PhyloP100		-0.99
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: rs5745635; hg19: chr7-81388042;