Genetic Variant AJAP1:p.Arg105Leu (chr1-4712184-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018836.4(AJAP1):c.314G>T(p.Arg105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AJAP1
NM_018836.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.56

Publications

2 publications found

Variant links:

Genes affected

AJAP1 (HGNC:30801): (adherens junctions associated protein 1) Enables beta-catenin binding activity. Involved in negative regulation of cell-matrix adhesion; negative regulation of wound healing; and regulation of polarized epithelial cell differentiation. Located in several cellular components, including adherens junction; basolateral plasma membrane; and cell-cell contact zone. Is spanning component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

AJAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28024969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AJAP1	NM_018836.4 link	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6	ENST00000378191.5	NP_061324.1	Q9UKB5
AJAP1	NM_001042478.2 link	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6		NP_001035943.1	Q9UKB5
AJAP1	XM_011541786.3 link	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 7		XP_011540088.1	Q9UKB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AJAP1	ENST00000378191.5 link	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6	1	NM_018836.4	ENSP00000367433.3	Q9UKB5
AJAP1	ENST00000378190.7 link	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6	5		ENSP00000367432.3	Q9UKB5
AJAP1	ENST00000466761.1 link	n.*19G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1412498

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700220

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000313

AC:

AN:

31996

American (AMR)

AF:

0.00

AC:

AN:

38484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24470

East Asian (EAS)

AF:

0.00

AC:

AN:

37842

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80456

European-Finnish (FIN)

AF:

0.0000244

AC:

AN:

41060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094100

Other (OTH)

AF:

0.00

AC:

AN:

58450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000576

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

0.099

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

L;L

PhyloP100

3.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.15

Sift

Benign

0.031

D;D

Sift4G

Benign

0.52

T;T

Polyphen

0.95

P;P

Vest4

0.35

MutPred

0.22

Loss of methylation at R105 (P = 0.0275);Loss of methylation at R105 (P = 0.0275);

MVP

0.54

MPC

1.3

ClinPred

0.86

GERP RS

5.2

Varity_R

0.24

gMVP

0.37

Mutation Taster

=87/13

polymorphism

(source)

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

Publications

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chr1-4712184-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over