NM_000601.6:c.1757+143G>A

Variant names:

• chr7-81706144-C-T
• rs5745752
• NM_000601.6:c.1757+143G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000601.6(HGF):​c.1757+143G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 743,018 control chromosomes in the GnomAD database, including 31,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5180 hom., cov: 31)
  • Exomes 𝑓: 0.30 (26806 hom.)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-81706144-C-T is Benign according to our data. Variant chr7-81706144-C-T is described in ClinVar as Benign. ClinVar VariationId is 1239121.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1757+143G>A		intron_variant	Intron 15 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1742+143G>A		intron_variant	Intron 15 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1757+143G>A		intron_variant	Intron 15 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38298 AN: 151538 Hom.: 5177 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.297 AC: 175532 AN: 591362 Hom.: 26806 AF XY: 0.299 AC XY: 94443 AN XY: 315664

African (AFR) AF: 0.141 AC: 2173 AN: 15426

American (AMR) AF: 0.260 AC: 7506 AN: 28814

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 5581 AN: 18090

East Asian (EAS) AF: 0.339 AC: 10977 AN: 32342

South Asian (SAS) AF: 0.341 AC: 19891 AN: 58268

European-Finnish (FIN) AF: 0.260 AC: 9842 AN: 37832

Middle Eastern (MID) AF: 0.314 AC: 1105 AN: 3524

European-Non Finnish (NFE) AF: 0.299 AC: 109477 AN: 365886

Other (OTH) AF: 0.288 AC: 8980 AN: 31180

GnomAD4 genome AF: 0.253 AC: 38297 AN: 151656 Hom.: 5180 Cov.: 31 AF XY: 0.253 AC XY: 18732 AN XY: 74082

African (AFR) AF: 0.148 AC: 6135 AN: 41408

American (AMR) AF: 0.267 AC: 4050 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1010 AN: 3464

East Asian (EAS) AF: 0.332 AC: 1709 AN: 5142

South Asian (SAS) AF: 0.370 AC: 1778 AN: 4802

European-Finnish (FIN) AF: 0.256 AC: 2694 AN: 10534

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 19983 AN: 67806

Other (OTH) AF: 0.265 AC: 558 AN: 2108

Alfa AF: 0.282 Hom.: 18648

Bravo AF: 0.250

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.90
CADD	Benign	0.10
DANN	Benign	0.55
PhyloP100		-1.5
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: rs5745752; hg19: chr7-81335460;