rs200271507

Positions:

• chr12-8847610-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_144670.6(A2ML1):​c.1745A>G​(p.Gln582Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,613,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.297

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011335194).
• BP6: Variant 12-8847610-A-G is Benign according to our data. Variant chr12-8847610-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 413818.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr12-8847610-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.1745A>G	p.Gln582Arg	missense_variant	15/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.1745A>G	p.Gln582Arg	missense_variant	15/36	1	NM_144670.6	ENSP00000299698	P1

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000503 AC: 125 AN: 248684 Hom.: 0 AF XY: 0.000422 AC XY: 57 AN XY: 134912

Gnomad AFR exome AF: 0.00706

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461358 Hom.: 1 Cov.: 30 AF XY: 0.000172 AC XY: 125 AN XY: 726978

Gnomad4 AFR exome AF: 0.00792

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74426

Gnomad4 AFR AF: 0.00729

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.00204

ESP6500AA AF: 0.00540 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000563 AC: 68

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2020	Variant summary: A2ML1 c.1745A>G (p.Gln582Arg) 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 0.0005 in 248684 control chromosomes, predominantly at a frequency of 0.0071 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1800-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 African or African-American origin. To our knowledge, no occurrence of c.1745A>G 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 benign. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2023	The p.Q582R variant (also known as c.1745A>G), located in coding exon 15 of the A2ML1 gene, results from an A to G substitution at nucleotide position 1745. The glutamine at codon 582 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2019	- -

A2ML1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

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	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	T;T;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.51	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.0090	B;.;.;.
Vest4		0.12
MVP		0.11
MPC		0.15
ClinPred		0.0065	T
GERP RS		1.3
Varity_R		0.064
gMVP		0.25

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: rs200271507; hg19: chr12-9000206;