rs267606555

Variant names:

• chr11-67490037-G-A
• rs267606555
• NM_003977.4:c.469-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-67490037-G-A
• chr11-67490037-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_003977.4(AIP):​c.469-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AIP NM_003977.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 8.17
• Publications: 1 publications found

Genes affected

AIP (HGNC:358): (aryl hydrocarbon receptor interacting protein) The protein encoded by this gene is a receptor for aryl hydrocarbons and a ligand-activated transcription factor. The encoded protein is found in the cytoplasm as part of a multiprotein complex, but upon binding of ligand is transported to the nucleus. This protein can regulate the expression of many xenobiotic metabolizing enzymes. Also, the encoded protein can bind specifically to and inhibit the activity of hepatitis B virus. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

MIR6752 (HGNC:50020): (microRNA 6752) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17824773 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 27, new splice context is: gccctggcacgtaccagcAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003977.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIP	NM_003977.4	MANE Select	c.469-1G>A		splice_acceptor intron	N/A	NP_003968.3	O00170
	AIP	NM_001302960.2		c.469-1G>A		splice_acceptor intron	N/A	NP_001289889.1	A0A804HJ38
	AIP	NM_001302959.2		c.292-1G>A		splice_acceptor intron	N/A	NP_001289888.1	A0A804HKL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIP	ENST00000279146.8	TSL:1 MANE Select	c.469-1G>A		splice_acceptor intron	N/A	ENSP00000279146.3	O00170
	AIP	ENST00000934218.1		c.559-1G>A		splice_acceptor intron	N/A	ENSP00000604277.1
	AIP	ENST00000872352.1		c.469-1G>A		splice_acceptor intron	N/A	ENSP00000542411.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447042 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718540

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 42644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 38922

South Asian (SAS) AF: 0.00 AC: 0 AN: 84094

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105876

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000655 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Somatotroph adenoma (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.2
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606555; hg19: chr11-67257508;