chr7-81757200-T-C

Variant names:

• chr7-81757200-T-C
• rs142045938
• NM_000601.6:c.471A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000601.6(HGF):​c.471A>G​(p.Pro157Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,542,856 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HGF NM_000601.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.672
• 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 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-81757200-T-C is Benign according to our data. Variant chr7-81757200-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227427.
• BP7: Synonymous conserved (PhyloP=0.672 with no splicing effect.

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.471A>G	p.Pro157Pro	synonymous	Exon 4 of 18	NP_000592.3
	HGF	NM_001010932.3		c.471A>G	p.Pro157Pro	synonymous	Exon 4 of 18	NP_001010932.1	P14210-3
	HGF	NM_001010931.3		c.471A>G	p.Pro157Pro	synonymous	Exon 4 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.471A>G	p.Pro157Pro	synonymous	Exon 4 of 18	ENSP00000222390.5	P14210-1
	HGF	ENST00000457544.7	TSL:1	c.471A>G	p.Pro157Pro	synonymous	Exon 4 of 18	ENSP00000391238.2	P14210-3
	HGF	ENST00000444829.7	TSL:1	c.471A>G	p.Pro157Pro	synonymous	Exon 4 of 8	ENSP00000389854.2	P14210-2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251388 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000144 AC: 200 AN: 1390664 Hom.: 0 Cov.: 24 AF XY: 0.000141 AC XY: 98 AN XY: 696632

African (AFR) AF: 0.00 AC: 0 AN: 32198

American (AMR) AF: 0.0000448 AC: 2 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 84838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5640

European-Non Finnish (NFE) AF: 0.000175 AC: 183 AN: 1046968

Other (OTH) AF: 0.000224 AC: 13 AN: 57934

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000221 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.8
DANN	Benign	0.74
PhyloP100		0.67

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: rs142045938; hg19: chr7-81386516;