chr10-46383496-C-A

Variant names:

• chr10-46383496-C-A
• rs1432933133
• NM_001098845.3:c.362C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001098845.3(ANXA8L1):​c.362C>A​(p.Ala121Asp) variant causes a missense change. In-silico tool predicts a pathogenic 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. A121V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 9)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: ANXA8L1 NM_001098845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 0 publications found

Genes affected

ANXA8L1 (HGNC:23334): (annexin A8 like 1) This gene encodes a member of the annexin family of evolutionarily conserved Ca2+ and phospholipid binding proteins. The encoded protein may function as an an anticoagulant that indirectly inhibits the thromboplastin-specific complex. Overexpression of this gene has been associated with acute myelocytic leukemia. A highly similar duplicated copy of this gene is found in close proximity on the long arm of chromosome 10. [provided by RefSeq, Apr 2014]

ENSG00000285402 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098845.3. 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
	ANXA8L1	NM_001098845.3	MANE Select	c.362C>A	p.Ala121Asp	missense	Exon 5 of 12	NP_001092315.2	Q5VT79-1
	ANXA8L1	NM_001278924.2		c.435+804C>A		intron	N/A	NP_001265853.1	Q5VT79-2
	ANXA8L1	NM_001278923.2		c.321+804C>A		intron	N/A	NP_001265852.1	B4DTF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA8L1	ENST00000619162.5	TSL:1 MANE Select	c.362C>A	p.Ala121Asp	missense	Exon 5 of 12	ENSP00000480221.1	Q5VT79-1
	ANXA8L1	ENST00000622769.4	TSL:1	c.435+804C>A		intron	N/A	ENSP00000483608.1	Q5VT79-2
	ANXA8L1	ENST00000584982.7	TSL:2	c.476C>A	p.Ala159Asp	missense	Exon 5 of 12	ENSP00000462716.2	A0A075B752

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD2 exomes AF: 0.00000666 AC: 1 AN: 150080 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000112 AC: 1 AN: 888922 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 450618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19712

American (AMR) AF: 0.00 AC: 0 AN: 30670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17872

East Asian (EAS) AF: 0.00 AC: 0 AN: 35056

South Asian (SAS) AF: 0.00 AC: 0 AN: 63532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2886

European-Non Finnish (NFE) AF: 0.00000158 AC: 1 AN: 633616

Other (OTH) AF: 0.00 AC: 0 AN: 39588

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 9

ExAC AF: 0.00000860 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.1	T
PhyloP100		5.2
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.77		Loss of MoRF binding (P = 0.041)
MVP		0.25
ClinPred		0.97	D
GERP RS		1.2
Varity_R		0.36
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1432933133; hg19: chr10-47754755;