chr5-90716735-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_032119.4(ADGRV1):c.9447+6G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000716 in 1,602,634 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032119.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000900 AC: 137AN: 152206Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000906 AC: 223AN: 246084Hom.: 0 AF XY: 0.000883 AC XY: 118AN XY: 133562
GnomAD4 exome AF: 0.000697 AC: 1011AN: 1450310Hom.: 3 Cov.: 28 AF XY: 0.000682 AC XY: 492AN XY: 721530
GnomAD4 genome AF: 0.000899 AC: 137AN: 152324Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 77AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
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The ADGRV1 c.9447+6G>A variant was not identified in the literature but was identified in dbSNP (ID: rs201481219) and ClinVar (classified as a VUS by EGL Genetics and as likely benign by Laboratory for Molecular Medicine and Division of Genomic Diagnostics at The Children's Hospital of Philadelphia). The variant was also identified in control databases in 246 of 277482 chromosomes at a frequency of 0.000887 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 32 of 10164 chromosomes (freq: 0.003148), Latino in 78 of 34728 chromosomes (freq: 0.002246), Other in 7 of 7030 chromosomes (freq: 0.000996), African in 19 of 24152 chromosomes (freq: 0.000787), European (non-Finnish) in 96 of 127122 chromosomes (freq: 0.000755), South Asian in 13 of 30042 chromosomes (freq: 0.000433) and European (Finnish) in 1 of 24812 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The c.9447+6G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However this splicing prediction has not been confirmed by RNA analysis. 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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ADGRV1: BP4, BS2 -
not specified Benign:2
c.9447+6G>A in intron 6 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (32/11530) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201481219). -
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Usher syndrome type 2C Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at