chr8-123688898-C-T

Position:

• chr8-123688898-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004306.4(ANXA13):​c.691G>A​(p.Asp231Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,882 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: ANXA13 NM_004306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07942939).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA13	NM_004306.4	c.691G>A	p.Asp231Asn	missense_variant	9/11	ENST00000419625.6	NP_004297.2
ANXA13	NM_001003954.3	c.814G>A	p.Asp272Asn	missense_variant	10/12		NP_001003954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA13	ENST00000419625.6	c.691G>A	p.Asp231Asn	missense_variant	9/11	1	NM_004306.4	ENSP00000390809.1
ANXA13	ENST00000262219.10	c.814G>A	p.Asp272Asn	missense_variant	10/12	1		ENSP00000262219.6

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000453 AC: 114 AN: 251456 Hom.: 0 AF XY: 0.000500 AC XY: 68 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000343 AC: 501 AN: 1461650 Hom.: 2 Cov.: 30 AF XY: 0.000369 AC XY: 268 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74442

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000412

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.814G>A (p.D272N) alteration is located in exon 10 (coding exon 10) of the ANXA13 gene. This alteration results from a G to A substitution at nucleotide position 814, causing the aspartic acid (D) at amino acid position 272 to be replaced by an asparagine (N). 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	0.19
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.087
Sift	Benign	0.16	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.54	P;P
Vest4		0.35
MVP		0.45
MPC		0.14
ClinPred		0.039	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144282673; hg19: chr8-124701138; COSMIC: COSV51622564;