chr9-115023974-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002160.4(TNC):āc.6494A>Gā(p.Gln2165Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000108 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_002160.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000207 AC: 52AN: 250754Hom.: 0 AF XY: 0.000295 AC XY: 40AN XY: 135438
GnomAD4 exome AF: 0.000112 AC: 164AN: 1461126Hom.: 0 Cov.: 31 AF XY: 0.000155 AC XY: 113AN XY: 726774
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74510
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: TNC c.6494A>G (p.Gln2165Arg) results in a conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant alters the second to last nucleotide of exon 27 adjacent to the intron 27 splice donor site. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 250754 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. To our knowledge, no occurrence of c.6494A>G in individuals affected with Deafness, Autosomal Dominant 56 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Autosomal dominant nonsyndromic hearing loss 56 Uncertain:1
PP3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at