11-67490085-C-G

Variant names:

• chr11-67490085-C-G
• rs2276020
• NM_003977.4:c.516C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003977.4(AIP):​c.516C>G​(p.Asp172Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,328 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D172D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 18 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.516C>G	p.Asp172Glu	missense	Exon 4 of 6	NP_003968.3	O00170
	AIP	NM_001302960.2		c.516C>G	p.Asp172Glu	missense	Exon 4 of 6	NP_001289889.1	A0A804HJ38
	AIP	NM_001302959.2		c.339C>G	p.Asp113Glu	missense	Exon 4 of 6	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.516C>G	p.Asp172Glu	missense	Exon 4 of 6	ENSP00000279146.3	O00170
	AIP	ENST00000934218.1		c.606C>G	p.Asp202Glu	missense	Exon 4 of 6	ENSP00000604277.1
	AIP	ENST00000872352.1		c.516C>G	p.Asp172Glu	missense	Exon 4 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459328 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725776

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111290

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.37
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.61	T
PhyloP100		-1.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.47
Sift	Benign	0.75	T
Sift4G	Benign	0.48	T
Vest4		0.50
MutPred		0.36		Loss of helix (P = 0.079)
MVP		0.73
MPC		1.1
ClinPred		0.91	D
GERP RS		-4.4
gMVP		0.37
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2276020; hg19: chr11-67257556;