12-8843328-AAG-A

Position:

• chr12-8843328-AAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_144670.6(A2ML1):​c.1444_1445delAG​(p.Ser482fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,614,136 control chromosomes in the GnomAD database, including 141 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.016 (78 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (63 hom.)
• Consequence: A2ML1 NM_144670.6 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.106

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-8843328-AAG-A is Benign according to our data. Variant chr12-8843328-AAG-A is described in ClinVar as [Benign]. Clinvar id is 241884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8843328-AAG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.1444_1445delAG	p.Ser482fs	frameshift_variant	12/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.1444_1445delAG	p.Ser482fs	frameshift_variant	12/36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.94_95delAG	p.Ser32fs	frameshift_variant	1/25	2		ENSP00000443174.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2461 AN: 152152 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00400 AC: 997 AN: 249508 Hom.: 30 AF XY: 0.00260 AC XY: 352 AN XY: 135372

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00162 AC: 2370 AN: 1461866 Hom.: 63 AF XY: 0.00130 AC XY: 945 AN XY: 727232

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0162 AC: 2461 AN: 152270 Hom.: 78 Cov.: 32 AF XY: 0.0152 AC XY: 1135 AN XY: 74468

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00206 Hom.: 4

Bravo AF: 0.0180

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: A2ML1 c.1444_1445delAG (p.Ser482ProfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 0.004 in 249508 control chromosomes, predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 29 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14250-folds over the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1444_1445delAG in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143864957; hg19: chr12-8995924;