12-8843160-A-G

Variant names:

• chr12-8843160-A-G
• rs7308106
• NM_144670.6:c.1275A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144670.6(A2ML1):​c.1275A>G​(p.Val425Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,613,954 control chromosomes in the GnomAD database, including 7,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V425V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.066 (494 hom., cov: 32)
  • Exomes 𝑓: 0.091 (6804 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.208
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-8843160-A-G is Benign according to our data. Variant chr12-8843160-A-G is described in ClinVar as Benign. ClinVar VariationId is 384677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.208 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0975 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.1275A>G	p.Val425Val	synonymous	Exon 12 of 36	NP_653271.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.1275A>G	p.Val425Val	synonymous	Exon 12 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.-76A>G		upstream_gene	N/A	ENSP00000443174.1

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10048 AN: 152176 Hom.: 494 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.0847

GnomAD2 exomes AF: 0.0711 AC: 17747 AN: 249524 AF XY: 0.0716

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0580

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.0906 AC: 132401 AN: 1461660 Hom.: 6804 Cov.: 32 AF XY: 0.0894 AC XY: 65034 AN XY: 727160

African (AFR) AF: 0.0145 AC: 484 AN: 33480

American (AMR) AF: 0.0582 AC: 2601 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3663 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0329 AC: 2837 AN: 86248

European-Finnish (FIN) AF: 0.0603 AC: 3221 AN: 53420

Middle Eastern (MID) AF: 0.116 AC: 669 AN: 5766

European-Non Finnish (NFE) AF: 0.102 AC: 113608 AN: 1111808

Other (OTH) AF: 0.0880 AC: 5312 AN: 60388

GnomAD4 genome AF: 0.0660 AC: 10044 AN: 152294 Hom.: 494 Cov.: 32 AF XY: 0.0626 AC XY: 4663 AN XY: 74456

African (AFR) AF: 0.0179 AC: 743 AN: 41572

American (AMR) AF: 0.0738 AC: 1128 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4828

European-Finnish (FIN) AF: 0.0547 AC: 581 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6766 AN: 68014

Other (OTH) AF: 0.0838 AC: 177 AN: 2112

Alfa AF: 0.0892 Hom.: 1530

Bravo AF: 0.0650

Asia WGS AF: 0.0130 AC: 48 AN: 3478

EpiCase AF: 0.0984

EpiControl AF: 0.101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.66
PhyloP100		-0.21
PromoterAI		0.0066	Neutral
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: rs7308106; hg19: chr12-8995756; COSMIC: COSV55290796; COSMIC: COSV55290796;