rs74582459

chr12-8851792-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144670.6(A2ML1):c.2243G>A(p.Gly748Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00076 in 1,614,036 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts 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. G748R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.89

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=0.005795121).
• BP6: Variant 12-8851792-G-A is Benign according to our data. Variant chr12-8851792-G-A is described in ClinVar as [Benign]. Clinvar id is 241889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000998 (152/152256) while in subpopulation EAS AF= 0.0262 (136/5188). AF 95% confidence interval is 0.0226. There are 2 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.2243G>A	p.Gly748Glu	missense_variant	19/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.2243G>A	p.Gly748Glu	missense_variant	19/36	1	NM_144670.6	P1
A2ML1	ENST00000541459.5	c.893G>A	p.Gly298Glu	missense_variant	8/25	2
A2ML1	ENST00000539547.5	c.770G>A	p.Gly257Glu	missense_variant	8/25	2

Frequencies

GnomAD3 genomes AF: 0.000993 AC: 151 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00148 AC: 368 AN: 249342 Hom.: 3 AF XY: 0.00139 AC XY: 188 AN XY: 135298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0191

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000735 AC: 1074 AN: 1461780 Hom.: 9 Cov.: 30 AF XY: 0.000729 AC XY: 530 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152256 Hom.: 2 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0262

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000986

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.00982 AC: 34 AN: 3478

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2020	Variant summary: A2ML1 c.2243G>A (p.Gly748Glu) results in a non-conservative amino acid change located in the Alpha-2-macroglobulin domain (IPR001599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 249342 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4750 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 East Asian origin. To our knowledge, no occurrence of c.2243G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

A2ML1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.58
MVP		0.24
MPC		0.60
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.75
gMVP		0.89

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: rs74582459; hg19: chr12-9004388;