NM_144670.6:c.2173G>A

Variant names:

• chr12-8850213-G-A
• rs192221816
• NM_144670.6:c.2173G>A

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.2173G>A​(p.Glu725Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.306
• Publications: 6 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=0.0058885515).
• BP6: Variant 12-8850213-G-A is Benign according to our data. Variant chr12-8850213-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413810.
• BS2: High AC in GnomAd4 at 188 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.2173G>A	p.Glu725Lys	missense	Exon 18 of 36	NP_653271.3
	A2ML1	NM_001282424.3		c.700G>A	p.Glu234Lys	missense	Exon 7 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.2173G>A	p.Glu725Lys	missense	Exon 18 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.823G>A	p.Glu275Lys	missense	Exon 7 of 25	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.700G>A	p.Glu234Lys	missense	Exon 7 of 25	ENSP00000438292.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00119 AC: 297 AN: 248864 AF XY: 0.00132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000989 AC: 1445 AN: 1461302 Hom.: 0 Cov.: 30 AF XY: 0.00101 AC XY: 736 AN XY: 726958

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.00154 AC: 69 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 188 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000743 AC: 64 AN: 86184

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53216

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000902 AC: 1003 AN: 1111826

Other (OTH) AF: 0.00176 AC: 106 AN: 60384

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74434

African (AFR) AF: 0.000385 AC: 16 AN: 41532

American (AMR) AF: 0.00340 AC: 52 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00127 Hom.: 3

Bravo AF: 0.00107

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00122 AC: 10

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	1	A2ML1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.31
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.065	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.040
MPC		0.12
ClinPred		0.016	T
GERP RS		2.3
Varity_R		0.10
gMVP		0.48
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192221816; hg19: chr12-9002809; COSMIC: COSV106094176; COSMIC: COSV106094176;