10-73383328-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001156.5(ANXA7):c.765A>T(p.Glu255Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,210 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 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
ANXA7
NM_001156.5 missense
NM_001156.5 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 2.21
Genes affected
ANXA7 (HGNC:545): (annexin A7) Annexin VII is a member of the annexin family of calcium-dependent phospholipid binding proteins.The Annexin VII gene contains 14 exons and spans approximately 34 kb of DNA. An alternatively spliced cassette exon results in two mRNA transcripts of 2.0 and 2.4 kb which are predicted to generate two protein isoforms differing in their N-terminal domain. The alternative splicing event is tissue specific and the mRNA containing the cassette exon is prevalent in brain, heart and skeletal muscle. The transcripts also differ in their 3'-non coding regions by the use of two alternative poly(A) signals. Annexin VII encodes a protein with a molecular weight of approximately 51 kDa with a unique, highly hydrophobic N-terminal domain of 167 amino acids and a conserved C-terminal region of 299 amino acids. The latter domain is composed of alternating hydrophobic and hydrophilic segments. Structural analysis of the protein suggests that Annexin VII is a membrane binding protein with diverse properties, including voltage-sensitive calcium channel activity, ion selectivity and membrane fusion. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANXA7 | NM_001156.5 | c.765A>T | p.Glu255Asp | missense_variant | 9/13 | ENST00000372921.10 | NP_001147.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANXA7 | ENST00000372921.10 | c.765A>T | p.Glu255Asp | missense_variant | 9/13 | 1 | NM_001156.5 | ENSP00000362012.4 | ||
ANXA7 | ENST00000372919.8 | c.831A>T | p.Glu277Asp | missense_variant | 10/14 | 1 | ENSP00000362010.4 | |||
ENSG00000233144 | ENST00000427492.1 | n.233T>A | non_coding_transcript_exon_variant | 2/2 | 2 | |||||
ANXA7 | ENST00000492380.1 | n.776A>T | non_coding_transcript_exon_variant | 8/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000480 AC: 12AN: 249894Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135080
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GnomAD4 exome AF: 0.000240 AC: 350AN: 1461028Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168AN XY: 726704
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2021 | The c.831A>T (p.E277D) alteration is located in exon 10 (coding exon 9) of the ANXA7 gene. This alteration results from a A to T substitution at nucleotide position 831, causing the glutamic acid (E) at amino acid position 277 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
0.83
.;Loss of sheet (P = 0.0817);
MVP
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at