rs1860926

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 1169145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8852296-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.2550C>A	p.Asp850Glu	missense_variant	20/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.2550C>A	p.Asp850Glu	missense_variant	20/36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.1200C>A	p.Asp400Glu	missense_variant	9/25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.1077C>A	p.Asp359Glu	missense_variant	9/25	2		ENSP00000438292.1

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

GnomAD3 exomes AF: 0.992 AC: 247429 AN: 249514 Hom.: 122775 AF XY: 0.994 AC XY: 134507 AN XY: 135358

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 SAS 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

Gnomad4 AFR exome AF: 0.880

Gnomad4 AMR exome AF: 0.993

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.992

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

Gnomad4 AFR AF: 0.882

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.975

Alfa AF: 0.995 Hom.: 110102

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.076	T;T;T
MetaRNN	Benign	9.5e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.2	N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.8	N;N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;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

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: rs1860926; hg19: chr12-9004892;