chr11-67490807-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2
The NM_001302960.2(AIP):c.799C>T(p.Gln267*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00103 in 1,612,406 control chromosomes in the GnomAD database, including 3 homozygotes. 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_001302960.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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AIP | NM_003977.4 | c.807C>T | p.Phe269Phe | synonymous_variant | Exon 6 of 6 | ENST00000279146.8 | NP_003968.3 | |
AIP | NM_001302960.2 | c.799C>T | p.Gln267* | stop_gained | Exon 6 of 6 | NP_001289889.1 | ||
AIP | NM_001302959.2 | c.630C>T | p.Phe210Phe | synonymous_variant | Exon 6 of 6 | NP_001289888.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000578 AC: 88AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000559 AC: 139AN: 248838Hom.: 0 AF XY: 0.000606 AC XY: 82AN XY: 135236
GnomAD4 exome AF: 0.00108 AC: 1571AN: 1460054Hom.: 3 Cov.: 32 AF XY: 0.00110 AC XY: 802AN XY: 726336
GnomAD4 genome AF: 0.000578 AC: 88AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:4
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This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548) -
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The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 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 (non-Finnish) in 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
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AIP: BP4, BP7 -
Somatotroph adenoma Uncertain:1Benign:1Other:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284] -
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Hereditary cancer-predisposing syndrome Benign:2
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
AIP-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