Genetic Variant AJAP1:p.Ala123Thr (chr1-4712237-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018836.4(AJAP1):c.367G>A(p.Ala123Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,534,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

AJAP1
NM_018836.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.101

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019340426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AJAP1	NM_018836.4 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 2 of 6	ENST00000378191.5	NP_061324.1	Q9UKB5
AJAP1	NM_001042478.2 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 2 of 6		NP_001035943.1	Q9UKB5
AJAP1	XM_011541786.3 link	c.367G>A	p.Ala123Thr	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.367G>A	p.Ala123Thr	missense_variant	Exon 2 of 6	1	NM_018836.4	ENSP00000367433.3	Q9UKB5
AJAP1	ENST00000378190.7 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 2 of 6	5		ENSP00000367432.3	Q9UKB5
AJAP1	ENST00000466761.1 link	n.*72G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000210

AC:

AN:

162168

AF XY:

0.000168

show subpopulations

Gnomad AFR exome

AF:

0.0000857

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000182

Gnomad NFE exome

AF:

0.000385

Gnomad OTH exome

AF:

0.000262

GnomAD4 exome

AF:

0.000553

AC:

765

AN:

1382224

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

358

AN XY:

681958

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30764

American (AMR)

AF:

0.00

AC:

AN:

32560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21758

East Asian (EAS)

AF:

0.00

AC:

AN:

38358

South Asian (SAS)

AF:

0.00

AC:

AN:

74324

European-Finnish (FIN)

AF:

0.0000963

AC:

AN:

41520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5468

European-Non Finnish (NFE)

AF:

0.000684

AC:

739

AN:

1080510

Other (OTH)

AF:

0.000369

AC:

AN:

56962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000355

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000705

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000387

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000249

AC:

ExAC

AF:

0.000135

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.367G>A (p.A123T) alteration is located in exon 2 (coding exon 2) of the AJAP1 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the alanine (A) at amino acid position 123 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.7

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.61

.;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N

PhyloP100

-0.10

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.090

Sift

Benign

0.52

T;T

Sift4G

Benign

0.79

T;T

Polyphen

0.0

B;B

Vest4

0.081

MVP

0.46

MPC

0.38

ClinPred

0.014

GERP RS

-0.43

Varity_R

0.060

gMVP

0.34

Mutation Taster

=95/5

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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1-4712237-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over