chr11-67490802-T-TACTTCAAGCGGGGCAAGGCCC

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PM4PP5_Very_StrongBS2

The NM_003977.4(AIP):c.805_825dupTTCAAGCGGGGCAAGGCCCAC(p.Phe269_His275dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,459,936 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A276A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

AIP
NM_003977.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 2.19

Publications

4 publications found

Variant links:

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]

AIP Gene-Disease associations (from GenCC):

growth hormone secreting pituitary adenoma 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial isolated pituitary adenoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pituitary gigantism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acromegaly
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

AIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM4

Nonframeshift variant in NON repetitive region in NM_003977.4.

PP5

Variant 11-67490802-T-TACTTCAAGCGGGGCAAGGCCC is Pathogenic according to our data. Variant chr11-67490802-T-TACTTCAAGCGGGGCAAGGCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 41208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 9 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIP	NM_003977.4	MANE Select	c.805_825dupTTCAAGCGGGGCAAGGCCCAC	p.Phe269_His275dup	conservative_inframe_insertion	Exon 6 of 6	NP_003968.3
AIP	NM_001302959.2		c.628_648dupTTCAAGCGGGGCAAGGCCCAC	p.Phe210_His216dup	conservative_inframe_insertion	Exon 6 of 6	NP_001289888.1
AIP	NM_001302960.2		c.797_817dupTTCAAGCGGGGCAAGGCCCAC	p.Leu266_Pro272dup	disruptive_inframe_insertion	Exon 6 of 6	NP_001289889.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIP	ENST00000279146.8	TSL:1 MANE Select	c.805_825dupTTCAAGCGGGGCAAGGCCCAC	p.Phe269_His275dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000279146.3
AIP	ENST00000934218.1		c.895_915dupTTCAAGCGGGGCAAGGCCCAC	p.Phe299_His305dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000604277.1
AIP	ENST00000872352.1		c.799_819dupTTCAAGCGGGGCAAGGCCCAC	p.Phe267_His273dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1459936

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5264

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111924

Other (OTH)

AF:

0.0000166

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Somatotroph adenoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=44/56

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over