5-151109844-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001155.5(ANXA6):c.1593A>C(p.Glu531Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,599,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ANXA6 NM_001155.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

Genes affected

ANXA6 (HGNC:544): (annexin A6) Annexin VI belongs to a family of calcium-dependent membrane and phospholipid binding proteins. Several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. The annexin VI gene is approximately 60 kbp long and contains 26 exons. It encodes a protein of about 68 kDa that consists of eight 68-amino acid repeats separated by linking sequences of variable lengths. It is highly similar to human annexins I and II sequences, each of which contain four such repeats. Annexin VI has been implicated in mediating the endosome aggregation and vesicle fusion in secreting epithelia during exocytosis. Alternatively spliced transcript variants have been described. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07281768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA6	NM_001155.5	c.1593A>C	p.Glu531Asp	missense_variant, splice_region_variant	22/26	ENST00000354546.10
ANXA6	NM_001363114.2	c.1575A>C	p.Glu525Asp	missense_variant, splice_region_variant	21/25
ANXA6	NM_001193544.2	c.1497A>C	p.Glu499Asp	missense_variant, splice_region_variant	21/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA6	ENST00000354546.10	c.1593A>C	p.Glu531Asp	missense_variant, splice_region_variant	22/26	1	NM_001155.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 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: 0.000385

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

GnomAD3 exomes AF: 0.0000349 AC: 8 AN: 229250 Hom.: 0 AF XY: 0.0000242 AC XY: 3 AN XY: 124020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000475

Gnomad SAS 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: 0.0000159 AC: 23 AN: 1446888 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 718888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000535

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jun 10, 2022

The c.1593A>C (p.E531D) alteration is located in exon 22 (coding exon 21) of the ANXA6 gene. This alteration results from a A to C substitution at nucleotide position 1593, causing the glutamic acid (E) at amino acid position 531 to be replaced by an aspartic acid (D). 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	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.027	D;D;D;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.038	B;.;.;P
Vest4		0.25
MutPred		0.39		Gain of helix (P = 0.132);.;.;.;
MVP		0.44
MPC		0.079
ClinPred		0.19	T
GERP RS		-1.5
Varity_R		0.24
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs767215473; hg19: chr5-150489405; COSMIC: COSV100636801; COSMIC: COSV100636801;