5-151101480-C-T

Position:

• chr5-151101480-C-T

Variant summary

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

The NM_001155.5(ANXA6):​c.1990G>A​(p.Ala664Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,409,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANXA6 NM_001155.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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=0.2495153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA6	NM_001155.5	c.1990G>A	p.Ala664Thr	missense_variant	26/26	ENST00000354546.10	NP_001146.2
ANXA6	NM_001363114.2	c.1972G>A	p.Ala658Thr	missense_variant	25/25		NP_001350043.1
ANXA6	NM_001193544.2	c.1894G>A	p.Ala632Thr	missense_variant	25/25		NP_001180473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA6	ENST00000354546.10	c.1990G>A	p.Ala664Thr	missense_variant	26/26	1	NM_001155.5	ENSP00000346550.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409500 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 696304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000539

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000151

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

Nov 24, 2024

The c.1990G>A (p.A664T) alteration is located in exon 26 (coding exon 25) of the ANXA6 gene. This alteration results from a G to A substitution at nucleotide position 1990, causing the alanine (A) at amino acid position 664 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.22	B;.;.;B
Vest4		0.23
MutPred		0.55		Loss of ubiquitination at K663 (P = 0.0504);.;.;.;
MVP		0.58
MPC		0.072
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.37
gMVP		0.35

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: rs1764548868; hg19: chr5-150481041;