rs11047499

chr12-8835642-G-Cchr12-8835642-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144670.6(A2ML1):c.619G>C(p.Gly207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,080 control chromosomes in the GnomAD database, including 335 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G207C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (173 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (162 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.222

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015576482).
• BP6: Variant 12-8835642-G-C is Benign according to our data. Variant chr12-8835642-G-C is described in ClinVar as [Benign]. Clinvar id is 120255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8835642-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.619G>C	p.Gly207Arg	missense_variant	6/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.619G>C	p.Gly207Arg	missense_variant	6/36	1	NM_144670.6	P1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3928 AN: 152118 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00654 AC: 1632 AN: 249422 Hom.: 81 AF XY: 0.00450 AC XY: 609 AN XY: 135302

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00271 AC: 3956 AN: 1461844 Hom.: 162 Cov.: 30 AF XY: 0.00227 AC XY: 1653 AN XY: 727222

Gnomad4 AFR exome AF: 0.0915

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.0258 AC: 3932 AN: 152236 Hom.: 173 Cov.: 33 AF XY: 0.0250 AC XY: 1859 AN XY: 74428

Gnomad4 AFR AF: 0.0892

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00164 Hom.: 3

Bravo AF: 0.0294

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0811 AC: 327

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00798 AC: 965

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2 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.619G>C (p.Gly207Arg) 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 956/120716 control chromosomes (44 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.088193 (865/9808). This frequency is about 22048 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a common benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory (via ClinVar) has 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	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Benign	0.83
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.025
Sift	Benign	0.12	T
Sift4G	Benign	0.41	T
Polyphen		0.027	B
Vest4		0.28
MVP		0.040
MPC		0.15
ClinPred		0.0014	T
GERP RS		0.99
Varity_R		0.12
gMVP		0.54

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: rs11047499; hg19: chr12-8988238; COSMIC: COSV55300981; COSMIC: COSV55300981;