rs1860926

Variant names:

• chr12-8852296-C-A
• rs1860926
• NM_144670.6:c.2550C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-8852296-C-A
• chr12-8852296-C-G
• chr12-8852296-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144670.6(A2ML1):​c.2550C>A​(p.Asp850Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,614,124 control chromosomes in the GnomAD database, including 797,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71161 hom., cov: 31)
  • Exomes 𝑓: 1.0 (726213 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.103
• Publications: 31 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: Orphanet, ClinGen, Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4884257E-7).
• BP6: Variant 12-8852296-C-A is Benign according to our data. Variant chr12-8852296-C-A is described in ClinVar as Benign. ClinVar VariationId is 1169145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.2550C>A	p.Asp850Glu	missense	Exon 20 of 36	NP_653271.3	A8K2U0-1
	A2ML1	NM_001282424.3		c.1077C>A	p.Asp359Glu	missense	Exon 9 of 25	NP_001269353.2	A8K2U0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.2550C>A	p.Asp850Glu	missense	Exon 20 of 36	ENSP00000299698.7	A8K2U0-1
	A2ML1	ENST00000541459.5	TSL:2	c.1200C>A	p.Asp400Glu	missense	Exon 9 of 25	ENSP00000443174.1	H0YGG5
	A2ML1	ENST00000539547.5	TSL:2	c.1077C>A	p.Asp359Glu	missense	Exon 9 of 25	ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes AF: 0.966 AC: 146898 AN: 152122 Hom.: 71113 Cov.: 31

Gnomad AFR AF: 0.882

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.975

GnomAD2 exomes AF: 0.992 AC: 247429 AN: 249514 AF XY: 0.994

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.997 AC: 1456877 AN: 1461884 Hom.: 726213 Cov.: 58 AF XY: 0.997 AC XY: 725076 AN XY: 727244

African (AFR) AF: 0.880 AC: 29461 AN: 33480

American (AMR) AF: 0.993 AC: 44427 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39697 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86242 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53414 AN: 53414

Middle Eastern (MID) AF: 0.994 AC: 5734 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111844 AN: 1112010

Other (OTH) AF: 0.992 AC: 59922 AN: 60396

GnomAD4 genome AF: 0.966 AC: 147001 AN: 152240 Hom.: 71161 Cov.: 31 AF XY: 0.966 AC XY: 71932 AN XY: 74440

African (AFR) AF: 0.882 AC: 36602 AN: 41500

American (AMR) AF: 0.984 AC: 15046 AN: 15296

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 68000 AN: 68036

Other (OTH) AF: 0.975 AC: 2062 AN: 2114

Alfa AF: 0.988 Hom.: 144012

Bravo AF: 0.959

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.890 AC: 3510

ESP6500EA AF: 1.00 AC: 8352

ExAC AF: 0.990 AC: 119575

Asia WGS AF: 0.990 AC: 3443 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.6
DANN	Benign	0.26
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.076	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.10
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.30		Gain of ubiquitination at K852 (P = 0.1278)
MPC		0.097
ClinPred		0.00089	T
GERP RS		2.0
Varity_R		0.041
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs1860926; hg19: chr12-9004892; COSMIC: COSV107349282; COSMIC: COSV107349282;