4-121683425-A-G

Position:

• chr4-121683425-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001154.4(ANXA5):​c.242T>C​(p.Ile81Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0033 in 1,611,744 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: ANXA5 NM_001154.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.71

Genes affected

ANXA5 (HGNC:543): (annexin A5) The Annexin 5 gene spans 29 kb containing 13 exons, and encodes a single transcript of approximately 1.6 kb and a protein product with a molecular weight of about 35 kDa.The protein encoded by this gene belongs to the annexin family of calcium-dependent phospholipid binding proteins some of which have been implicated in membrane-related events along exocytotic and endocytotic pathways. Annexin 5 is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and a potential role in cellular signal transduction, inflammation, growth and differentiation. Annexin 5 has also been described as placental anticoagulant protein I, vascular anticoagulant-alpha, endonexin II, lipocortin V, placental protein 4 and anchorin CII. Polymorphisms in this gene have been implicated in various obstetric complications. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02133289).
• BP6: Variant 4-121683425-A-G is Benign according to our data. Variant chr4-121683425-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 778158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA5	NM_001154.4	c.242T>C	p.Ile81Thr	missense_variant	5/13	ENST00000296511.10
ANXA5	XM_017008141.3	c.242T>C	p.Ile81Thr	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA5	ENST00000296511.10	c.242T>C	p.Ile81Thr	missense_variant	5/13	1	NM_001154.4	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 430 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00216 AC: 541 AN: 249952 Hom.: 2 AF XY: 0.00223 AC XY: 302 AN XY: 135142

Gnomad AFR exome AF: 0.000682

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000921

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00335 AC: 4896 AN: 1459426 Hom.: 11 Cov.: 29 AF XY: 0.00337 AC XY: 2445 AN XY: 726078

Gnomad4 AFR exome AF: 0.000510

Gnomad4 AMR exome AF: 0.00270

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000931

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74482

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00407

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00297

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		0.97	D;P
Vest4		0.77
MVP		0.89
MPC		0.75
ClinPred		0.028	T
GERP RS		6.0
Varity_R		0.77
gMVP		0.62

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: rs41278081; hg19: chr4-122604580;