12-8863977-A-G

Variant names:

• chr12-8863977-A-G
• rs10219561
• NM_144670.6:c.3686A>G

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.3686A>G​(p.His1229Arg) 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 1,612,776 control chromosomes in the GnomAD database, including 797,653 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1229C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.97 (71742 hom., cov: 31)
  • Exomes 𝑓: 1.0 (725911 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46
• Publications: 21 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

ENSG00000282022 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.4597877E-6).
• BP6: Variant 12-8863977-A-G is Benign according to our data. Variant chr12-8863977-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3686A>G	p.His1229Arg	missense_variant	Exon 29 of 36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.3686A>G	p.His1229Arg	missense_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.2336A>G	p.His779Arg	missense_variant	Exon 18 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.2213A>G	p.His738Arg	missense_variant	Exon 18 of 25	2		ENSP00000438292.1
ENSG00000282022	ENST00000631830.1	n.322-5701T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147533 AN: 152160 Hom.: 71687 Cov.: 31

Gnomad AFR AF: 0.895

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.978

GnomAD2 exomes AF: 0.993 AC: 247340 AN: 249146 AF XY: 0.995

Gnomad AFR exome AF: 0.896

Gnomad AMR exome AF: 0.995

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: 0.997

GnomAD4 exome AF: 0.997 AC: 1455922 AN: 1460498 Hom.: 725911 Cov.: 55 AF XY: 0.997 AC XY: 724670 AN XY: 726558

African (AFR) AF: 0.890 AC: 29749 AN: 33442

American (AMR) AF: 0.994 AC: 44471 AN: 44724

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

East Asian (EAS) AF: 0.999 AC: 39645 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86143 AN: 86150

European-Finnish (FIN) AF: 1.00 AC: 53405 AN: 53406

Middle Eastern (MID) AF: 0.996 AC: 4751 AN: 4768

European-Non Finnish (NFE) AF: 1.00 AC: 1111758 AN: 1111914

Other (OTH) AF: 0.993 AC: 59864 AN: 60260

GnomAD4 genome AF: 0.970 AC: 147649 AN: 152278 Hom.: 71742 Cov.: 31 AF XY: 0.971 AC XY: 72268 AN XY: 74452

African (AFR) AF: 0.895 AC: 37175 AN: 41542

American (AMR) AF: 0.987 AC: 15099 AN: 15296

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4818

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

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68022 AN: 68036

Other (OTH) AF: 0.978 AC: 2069 AN: 2116

Alfa AF: 0.991 Hom.: 126282

Bravo AF: 0.965

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.901 AC: 3472

ESP6500EA AF: 1.00 AC: 8248

ExAC AF: 0.991 AC: 119721

Asia WGS AF: 0.995 AC: 3460 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.9
DANN	Benign	0.85
DEOGEN2	Benign	0.0025	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.026	T;T;T
MetaRNN	Benign	0.0000015	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.7	N;.;.
PhyloP100		1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.6	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.016
MPC		0.13
ClinPred		0.0071	T
GERP RS		-1.1
Varity_R		0.044
gMVP		0.31
Mutation Taster		=79/21	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: rs10219561; hg19: chr12-9016573; COSMIC: COSV55285955; COSMIC: COSV55285955;