10-73376187-C-A

Variant names:

• chr10-73376187-C-A
• rs146521289
• NM_001156.5:c.1309G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001156.5(ANXA7):​c.1309G>T​(p.Ala437Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,444,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ANXA7 NM_001156.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 5 publications found

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]

ENSG00000233144 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024671197).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001156.5. 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
	ANXA7	NM_001156.5	MANE Select	c.1309G>T	p.Ala437Ser	missense	Exon 13 of 13	NP_001147.1	P20073-2
	ANXA7	NM_004034.4		c.1375G>T	p.Ala459Ser	missense	Exon 14 of 14	NP_004025.1	P20073-1
	ANXA7	NM_001320880.2		c.1255G>T	p.Ala419Ser	missense	Exon 13 of 13	NP_001307809.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA7	ENST00000372921.10	TSL:1 MANE Select	c.1309G>T	p.Ala437Ser	missense	Exon 13 of 13	ENSP00000362012.4	P20073-2
	ANXA7	ENST00000372919.8	TSL:1	c.1375G>T	p.Ala459Ser	missense	Exon 14 of 14	ENSP00000362010.4	P20073-1
	ANXA7	ENST00000961271.1		c.1399G>T	p.Ala467Ser	missense	Exon 14 of 14	ENSP00000631330.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000251 AC: 6 AN: 238878 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000485 AC: 7 AN: 1444606 Hom.: 0 Cov.: 31 AF XY: 0.00000557 AC XY: 4 AN XY: 717878

African (AFR) AF: 0.00 AC: 0 AN: 32926

American (AMR) AF: 0.000140 AC: 6 AN: 42984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39112

South Asian (SAS) AF: 0.00 AC: 0 AN: 81308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104186

Other (OTH) AF: 0.0000168 AC: 1 AN: 59628

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.058
DANN	Benign	0.65
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.075	N
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.044
Sift	Benign	0.67	T
Sift4G	Benign	0.72	T
Polyphen		0.019	B
Vest4		0.065
MutPred		0.32		Gain of ubiquitination at K464 (P = 0.1096)
MVP		0.20
MPC		0.045
ClinPred		0.026	T
GERP RS		-7.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146521289; hg19: chr10-75135945;