chr12-8834689-G-A

Variant names:

• chr12-8834689-G-A
• rs73037000
• NM_144670.6:c.483+7G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144670.6(A2ML1):​c.483+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,614,042 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (75 hom.)
• Consequence: A2ML1 NM_144670.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002828
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.168
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-8834689-G-A is Benign according to our data. Variant chr12-8834689-G-A is described in ClinVar as [Benign]. Clinvar id is 241910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 930 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.483+7G>A		splice_region_variant, intron_variant	Intron 5 of 35	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.483+7G>A		splice_region_variant, intron_variant	Intron 5 of 35	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000537546.1	n.314G>A		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00655 AC: 1634 AN: 249462 AF XY: 0.00649

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00788 AC: 11516 AN: 1461742 Hom.: 75 Cov.: 30 AF XY: 0.00763 AC XY: 5548 AN XY: 727186

African (AFR) AF: 0.00114 AC: 38 AN: 33472

American (AMR) AF: 0.00336 AC: 150 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00151 AC: 130 AN: 86242

European-Finnish (FIN) AF: 0.0158 AC: 842 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00899 AC: 9997 AN: 1111920

Other (OTH) AF: 0.00565 AC: 341 AN: 60390

GnomAD4 genome AF: 0.00611 AC: 930 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74472

African (AFR) AF: 0.00113 AC: 47 AN: 41556

American (AMR) AF: 0.00360 AC: 55 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00806 AC: 548 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00708 Hom.: 2

Bravo AF: 0.00552

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00806

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A2ML1: BS1, BS2 -

Jul 06, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The A2ML1 c.483+7G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 838/120722 control chromosomes (9 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.01648 (109/6614). This frequency is about 4120 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.79
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs73037000; hg19: chr12-8987285; COSMIC: COSV100229123; COSMIC: COSV100229123;