1-4712163-C-T

Variant names:

• chr1-4712163-C-T
• rs780806292
• NM_018836.4:c.293C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018836.4(AJAP1):​c.293C>T​(p.Ala98Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000383 in 1,564,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AJAP1 NM_018836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059459835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AJAP1	NM_018836.4	c.293C>T	p.Ala98Val	missense_variant	Exon 2 of 6	ENST00000378191.5	NP_061324.1
AJAP1	NM_001042478.2	c.293C>T	p.Ala98Val	missense_variant	Exon 2 of 6		NP_001035943.1
AJAP1	XM_011541786.3	c.293C>T	p.Ala98Val	missense_variant	Exon 2 of 7		XP_011540088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AJAP1	ENST00000378191.5	c.293C>T	p.Ala98Val	missense_variant	Exon 2 of 6	1	NM_018836.4	ENSP00000367433.3
AJAP1	ENST00000378190.7	c.293C>T	p.Ala98Val	missense_variant	Exon 2 of 6	5		ENSP00000367432.3
AJAP1	ENST00000466761.1	n.296C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 171320 AF XY: 0.0000105

Gnomad AFR exome AF: 0.000211

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412470 Hom.: 0 Cov.: 37 AF XY: 0.00000143 AC XY: 1 AN XY: 700154

African (AFR) AF: 0.0000624 AC: 2 AN: 32048

American (AMR) AF: 0.00 AC: 0 AN: 38126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24654

East Asian (EAS) AF: 0.00 AC: 0 AN: 37722

South Asian (SAS) AF: 0.00 AC: 0 AN: 80782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093434

Other (OTH) AF: 0.0000171 AC: 1 AN: 58460

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74290

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000870 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.293C>T (p.A98V) alteration is located in exon 2 (coding exon 2) of the AJAP1 gene. This alteration results from a C to T substitution at nucleotide position 293, causing the alanine (A) at amino acid position 98 to be replaced by a valine (V). 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	0.099
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
PhyloP100		2.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.027
Sift	Benign	0.098	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0050	B;B
Vest4		0.094
MutPred		0.15		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.37
MPC		0.40
ClinPred		0.043	T
GERP RS		4.3
Varity_R		0.065
gMVP		0.15
Mutation Taster		=92/8	polymorphism

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: rs780806292; hg19: chr1-4772223;