7-81762824-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000601.6(HGF):c.137C>T(p.Ala46Val) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,596,858 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000601.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00133 AC: 202AN: 151986Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00178 AC: 446AN: 250740Hom.: 0 AF XY: 0.00179 AC XY: 242AN XY: 135536
GnomAD4 exome AF: 0.00182 AC: 2632AN: 1444754Hom.: 4 Cov.: 27 AF XY: 0.00176 AC XY: 1269AN XY: 719900
GnomAD4 genome AF: 0.00133 AC: 202AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
The HGF p.Ala46Val variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs150267054), ClinVar (classified as a VUS by Illumina for Nonsyndromic Hearing Loss, Mixed and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS and likely benign). The variant was also identified in control databases in 482 of 282092 chromosomes at a frequency of 0.001709 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 53 of 10362 chromosomes (freq: 0.005115), European (Finnish) in 66 of 25094 chromosomes (freq: 0.00263), European (non-Finnish) in 320 of 128720 chromosomes (freq: 0.002486), Other in 5 of 7206 chromosomes (freq: 0.000694), Latino in 22 of 35338 chromosomes (freq: 0.000623), South Asian in 10 of 30548 chromosomes (freq: 0.000327) and African in 6 of 24922 chromosomes (freq: 0.000241) but was not observed in the East Asian population. The p.Ala46 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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This variant is associated with the following publications: (PMID: 29924831) -
Nonsyndromic Hearing Loss, Mixed Uncertain:1
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not specified Benign:1
p.Ala46Val in exon 2 of HGF: This variant is not expected to have clinical signi ficance because it has been identified in 0.3% (196/64768) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs150267054). -
HGF-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at