rs200271507

Variant names:

• chr12-8847610-A-G
• rs200271507
• NM_144670.6:c.1745A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q582Q) has been classified as Likely benign.

• 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
• Publications: 2 publications found

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]

A2ML1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 413818.
• BS2: High AC in GnomAd4 at 313 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144670.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.1745A>G	p.Gln582Arg	missense	Exon 15 of 36	NP_653271.3
	A2ML1	NM_001282424.3		c.272A>G	p.Gln91Arg	missense	Exon 4 of 25	NP_001269353.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.1745A>G	p.Gln582Arg	missense	Exon 15 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.395A>G	p.Gln132Arg	missense	Exon 4 of 25	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.272A>G	p.Gln91Arg	missense	Exon 4 of 25	ENSP00000438292.1

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

GnomAD2 exomes AF: 0.000503 AC: 125 AN: 248684 AF XY: 0.000422

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 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

African (AFR) AF: 0.00792 AC: 265 AN: 33446

American (AMR) AF: 0.000269 AC: 12 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111782

Other (OTH) AF: 0.000414 AC: 25 AN: 60378

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

African (AFR) AF: 0.00729 AC: 303 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000564 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	A2ML1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N
PhyloP100		0.30
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.071
Sift	Benign	0.33	T
Sift4G	Benign	0.41	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200271507; hg19: chr12-9000206; COSMIC: COSV106094184; COSMIC: COSV106094184;