rs641081

Variant names:

• chr11-67490352-C-A
• rs641081
• NM_003977.4:c.682C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-67490352-C-A
• chr11-67490352-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003977.4(AIP):​c.682C>A​(p.Gln228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,612,358 control chromosomes in the GnomAD database, including 771,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q228R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (59219 hom., cov: 31)
  • Exomes 𝑓: 0.98 (712551 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.30
• Publications: 51 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.653613E-7).
• BP6: Variant 11-67490352-C-A is Benign according to our data. Variant chr11-67490352-C-A is described in ClinVar as Benign. ClinVar VariationId is 259205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

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.682C>A	p.Gln228Lys	missense	Exon 5 of 6	NP_003968.3	O00170
	AIP	NM_001302960.2		c.682C>A	p.Gln228Lys	missense	Exon 5 of 6	NP_001289889.1	A0A804HJ38
	AIP	NM_001302959.2		c.505C>A	p.Gln169Lys	missense	Exon 5 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.682C>A	p.Gln228Lys	missense	Exon 5 of 6	ENSP00000279146.3	O00170
	AIP	ENST00000934218.1		c.772C>A	p.Gln258Lys	missense	Exon 5 of 6	ENSP00000604277.1
	AIP	ENST00000872352.1		c.676C>A	p.Gln226Lys	missense	Exon 5 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes AF: 0.854 AC: 129700 AN: 151904 Hom.: 59183 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.893

GnomAD2 exomes AF: 0.962 AC: 239149 AN: 248548 AF XY: 0.972

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.980

GnomAD4 exome AF: 0.985 AC: 1438064 AN: 1460336 Hom.: 712551 Cov.: 77 AF XY: 0.987 AC XY: 716902 AN XY: 726442

African (AFR) AF: 0.490 AC: 16395 AN: 33480

American (AMR) AF: 0.970 AC: 43362 AN: 44716

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.999 AC: 86169 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 51917 AN: 51918

Middle Eastern (MID) AF: 0.977 AC: 5638 AN: 5768

European-Non Finnish (NFE) AF: 0.998 AC: 1110297 AN: 1111982

Other (OTH) AF: 0.968 AC: 58456 AN: 60378

GnomAD4 genome AF: 0.854 AC: 129792 AN: 152022 Hom.: 59219 Cov.: 31 AF XY: 0.860 AC XY: 63868 AN XY: 74302

African (AFR) AF: 0.496 AC: 20529 AN: 41386

American (AMR) AF: 0.938 AC: 14326 AN: 15266

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5142 AN: 5144

South Asian (SAS) AF: 0.999 AC: 4818 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10608 AN: 10608

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67827 AN: 68010

Other (OTH) AF: 0.894 AC: 1885 AN: 2108

Alfa AF: 0.939 Hom.: 145748

Bravo AF: 0.836

TwinsUK AF: 0.999 AC: 3705

ALSPAC AF: 0.997 AC: 3843

ESP6500AA AF: 0.517 AC: 2277

ESP6500EA AF: 0.997 AC: 8560

ExAC AF: 0.954 AC: 115509

Asia WGS AF: 0.977 AC: 3399 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.997

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Somatotroph adenoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.95	T
PhyloP100		1.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.089
MPC		0.46
ClinPred		0.0016	T
GERP RS		1.1
gMVP		0.31
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs641081; hg19: chr11-67257823; COSMIC: COSV54161477; COSMIC: COSV54161477;