rs61921916

chr12-8838341-C-Achr12-8838341-C-T

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.861C>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,612,544 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D287G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (85 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0420

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=0.00356704).
• BP6: Variant 12-8838341-C-A is Benign according to our data. Variant chr12-8838341-C-A is described in ClinVar as [Benign]. Clinvar id is 120256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8838341-C-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 1070 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.861C>A	p.Asp287Glu	missense_variant	9/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.861C>A	p.Asp287Glu	missense_variant	9/36	1	NM_144670.6	P1

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1070 AN: 152172 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00770 AC: 1916 AN: 248948 Hom.: 11 AF XY: 0.00768 AC XY: 1037 AN XY: 135048

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00151

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00630

GnomAD4 exome AF: 0.0102 AC: 14894 AN: 1460254 Hom.: 85 Cov.: 30 AF XY: 0.00988 AC XY: 7176 AN XY: 726430

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.00547

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00703 AC: 1071 AN: 152290 Hom.: 8 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74470

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00976 Hom.: 4

Bravo AF: 0.00718

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00154 AC: 6

ESP6500EA AF: 0.0142 AC: 118

ExAC AF: 0.00744 AC: 899

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00922

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

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.861C>A (p.Asp287Glu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 898/120478 control chromosomes (5 homozygotes) from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.011976 (798/66632). This frequency is about 2994 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 (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as benign. -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	0.075
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.034
Sift	Benign	0.040	D
Sift4G	Benign	0.16	T
Polyphen		0.78	P
Vest4		0.32
MutPred		0.29		Gain of sheet (P = 0.0827);
MVP		0.17
MPC		0.19
ClinPred		0.0050	T
GERP RS		2.9
Varity_R		0.13
gMVP		0.75

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: rs61921916; hg19: chr12-8990937; COSMIC: COSV55290783; COSMIC: COSV55290783;