12-8823009-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144670.6(A2ML1):c.63-173A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,002 control chromosomes in the GnomAD database, including 6,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6201 hom., cov: 32)
• Consequence: A2ML1 NM_144670.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

Genes affected

A2ML1 (HGNC:23336): (alpha-2-macroglobulin like 1) This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

A2ML1-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-8823009-A-G is Benign according to our data. Variant chr12-8823009-A-G is described in ClinVar as [Benign]. Clinvar id is 561550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.63-173A>G		intron_variant		ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.63-173A>G		intron_variant		1	NM_144670.6	P1
A2ML1-AS1	ENST00000537288.1	n.286+7653T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41809 AN: 151884 Hom.: 6196 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.214

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.275 AC: 41830 AN: 152002 Hom.: 6201 Cov.: 32 AF XY: 0.283 AC XY: 20981 AN XY: 74266

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.218

Alfa AF: 0.267 Hom.: 5737

Bravo AF: 0.261

Asia WGS AF: 0.433 AC: 1504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.2
Dann	Benign	0.39

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: rs7297690; hg19: chr12-8975605; COSMIC: COSV55289772; COSMIC: COSV55289772;