rs142219499

chr12-8843213-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.1328G>A(p.Arg443Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.540

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 (MetaRNN=0.006997049).
• BP6: Variant 12-8843213-G-A is Benign according to our data. Variant chr12-8843213-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 413812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.1328G>A	p.Arg443Gln	missense_variant	12/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.1328G>A	p.Arg443Gln	missense_variant	12/36	1	NM_144670.6	P1
A2ML1	ENST00000541459.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000212 AC: 53 AN: 249580 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135406

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727242

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74426

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0152 Hom.: 857

Bravo AF: 0.000257

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2021	Variant summary: A2ML1 c.1328G>A (p.Arg443Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 249580 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 300 fold of 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 Latino origin. To our knowledge, no occurrence of c.1328G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 16, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.052
Dann	Benign	0.85
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.40	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.034
Sift	Benign	0.54	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.059
MVP		0.055
MPC		0.12
ClinPred		0.0027	T
GERP RS		-4.7
Varity_R		0.028
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs142219499; hg19: chr12-8995809; COSMIC: COSV55294745; COSMIC: COSV55294745;