8-123698450-A-G

Variant names:

• chr8-123698450-A-G
• rs1239518976
• NM_004306.4:c.296T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004306.4(ANXA13):​c.296T>C​(p.Met99Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ANXA13 NM_004306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

Genes affected

ANXA13 (HGNC:536): (annexin A13) This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. The specific function of this gene has not yet been determined; however, it is associated with the plasma membrane of undifferentiated, proliferating endothelial cells and differentiated villus enterocytes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ENSG00000253286 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004306.4. 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
	ANXA13	NM_004306.4	MANE Select	c.296T>C	p.Met99Thr	missense	Exon 4 of 11	NP_004297.2	P27216-1
	ANXA13	NM_001003954.3		c.419T>C	p.Met140Thr	missense	Exon 5 of 12	NP_001003954.1	P27216-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA13	ENST00000419625.6	TSL:1 MANE Select	c.296T>C	p.Met99Thr	missense	Exon 4 of 11	ENSP00000390809.1	P27216-1
	ANXA13	ENST00000262219.10	TSL:1	c.419T>C	p.Met140Thr	missense	Exon 5 of 12	ENSP00000262219.6	P27216-2
	ANXA13	ENST00000862979.1		c.419T>C	p.Met140Thr	missense	Exon 5 of 11	ENSP00000533038.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.29
Sift	Benign	0.052	T
Sift4G	Uncertain	0.049	D
Polyphen		0.67	P
Vest4		0.60
MutPred		0.80		Loss of stability (P = 0.0233)
MVP		0.53
MPC		0.22
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.71
gMVP		0.84
Mutation Taster		=45/55	disease causing

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: rs1239518976; hg19: chr8-124710690;