X-67721909-C-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000044.6(AR):c.2395C>G(p.Gln799Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00149 in 1,209,115 control chromosomes in the GnomAD database, including 2 homozygotes. There are 571 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000044.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00130 AC: 144AN: 111074Hom.: 0 Cov.: 22 AF XY: 0.00117 AC XY: 39AN XY: 33258
GnomAD3 exomes AF: 0.00140 AC: 256AN: 183191Hom.: 0 AF XY: 0.00127 AC XY: 86AN XY: 67727
GnomAD4 exome AF: 0.00151 AC: 1659AN: 1098041Hom.: 2 Cov.: 31 AF XY: 0.00146 AC XY: 532AN XY: 363431
GnomAD4 genome AF: 0.00130 AC: 144AN: 111074Hom.: 0 Cov.: 22 AF XY: 0.00117 AC XY: 39AN XY: 33258
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Benign:1
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The AR p.Q799E variant was identified in the literature in multiple patients with androgen insensitivity syndrome (AIS), including the complete, partial and mild forms (Batch_1992_PMID:1307250; Petroli_2017_PMID:29237170; Jääskeläinen_2006_PMID:16595706; Hughes_2012_PMID:23044881). The p.Q799E variant was also identified in a male azoospermic patient and a male with prostate cancer (Wang_1998_PMID:9851768; Evans_1996_PMID:8628719). The variant was identified in dbSNP (ID: rs137852591), LOVD 3.0, Cosmic and ClinVar (classified as likely pathogenic by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was also found in the Cambridge AR Mutation Database in association with mild AIS and partial AIS (Hughes_2012_PMID:23044881). The variant was identified in control databases in 305 of 204870 chromosomes (104 hemizygous) at a frequency of 0.001489 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 51 of 18607 chromosomes (freq: 0.002741), European (non-Finnish) in 229 of 92423 chromosomes (freq: 0.002478), Ashkenazi Jewish in 11 of 7652 chromosomes (freq: 0.001438), Other in 6 of 5319 chromosomes (freq: 0.001128), Latino in 6 of 28040 chromosomes (freq: 0.000214), African in 1 of 18937 chromosomes (freq: 0.000053) and South Asian in 1 of 19071 chromosomes (freq: 0.000052), but was not observed in the East Asian population. The p.Q799E variant was identiifed in combination with a p.C807F variant in a female with complete AIS; functional studies of these variant indicated that the p.Q799E variant was not harmful on its own but had a synergistic negative effect when found as a double mutant with the p.C807F variant (Petroli_2017_PMID:29237170). Petroli et al. (2017) also identified the p.Q799E variant as a double mutant with p.F726V in another patient with AIS, suggesting that the p.Q799E variant may modulate or contribute to the AIS phenotype. Despite being found in the ligand binding domain, multiple functional studies have not found any ligand binding defects from this variant, and the effect of this variant on receptor trans-activation function has been minimal or insignificant compared to wildtype (Wang_1998_PMID:9851768; Bevan_1995_PMID:8824883; Jääskeläinen_2006_PMID:16595706). The p.Gln799 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is classified as a variant of uncertain significance, although this variant may contribute to AIS when found in combination with other AR variants. -
AR: BS2 -
Partial androgen insensitivity syndrome Pathogenic:1
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Malignant tumor of prostate Pathogenic:1
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not specified Uncertain:1
Variant summary: AR c.2395C>G (p.Gln799Glu) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 183191 control chromosomes to include both hemizygous males and heterozygous females. This frequency does not allow conclusions about variant significance, although pointing to a benign outcome. c.2395C>G has been reported in the literature in settings of females with partial androgen insensitivity (example, Batch_1992), in combination with a different AR gene variant p.Cys807Phe in a female with complete androgen insensitivity (example, Petroli_2017) and in other settings such as azoospermic/infertile males (example, Wang_1998, Hiort_2000). These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function (example, Wang_1998, Petroli_2017). The most pronounced variant effect results in normal ability to bind androgen receptor (Wang_1998, Petroli_2017) and conflicting results in transactivation activity ranging from a slight reduction to normal levels (Wang_1998, Petroli_2017). Furthermore, a recent report has identified that a complex allele combination of this variant with p.Cys807Phe results in a deleterious outcome thereby questioning the role of this variant in isolation in the associated pathophysiology of disease (Petroli_2017). The following publications have been ascertained in the context of this evaluation (PMID: 1307250, 10946887, 29237170, 9921903). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Male infertility Uncertain:1
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Androgen resistance syndrome;C1839259:Kennedy disease Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at