rs73037000

chr12-8834689-G-A

Variant summary

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

The NM_144670.6(A2ML1):c.483+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,614,042 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (75 hom.)
• Consequence: A2ML1 NM_144670.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002828
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.168

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-8834689-G-A is Benign according to our data. Variant chr12-8834689-G-A is described in ClinVar as [Benign]. Clinvar id is 241910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8834689-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 930 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.483+7G>A		splice_region_variant, intron_variant		ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.483+7G>A		splice_region_variant, intron_variant		1	NM_144670.6	P1
A2ML1	ENST00000537546.1	n.314G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00655 AC: 1634 AN: 249462 Hom.: 14 AF XY: 0.00649 AC XY: 879 AN XY: 135338

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00788 AC: 11516 AN: 1461742 Hom.: 75 Cov.: 30 AF XY: 0.00763 AC XY: 5548 AN XY: 727186

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00336

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.00899

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00611 AC: 930 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74472

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00708 Hom.: 2

Bravo AF: 0.00552

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00806

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The A2ML1 c.483+7G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 838/120722 control chromosomes (9 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.01648 (109/6614). This frequency is about 4120 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	A2ML1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2017	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	-0.88
Cadd	Benign	3.5
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs73037000; hg19: chr12-8987285; COSMIC: COSV100229123; COSMIC: COSV100229123;