rs144686314

Variant names:

• chr12-8863966-GGC-G
• rs144686314
• NM_144670.6:c.3676_3677delGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_144670.6(A2ML1):​c.3676_3677delGC​(p.Ala1226GlnfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0475 in 1,613,182 control chromosomes in the GnomAD database, including 2,054 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1226A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.036 (134 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1920 hom.)
• Consequence: A2ML1 NM_144670.6 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 1.20
• Publications: 11 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 -16 ACMG points.

• BP6: Variant 12-8863966-GGC-G is Benign according to our data. Variant chr12-8863966-GGC-G is described in ClinVar as Benign. ClinVar VariationId is 413822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0575 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.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift	Exon 29 of 36	NP_653271.3
	A2ML1	NM_001282424.3		c.2203_2204delGC	p.Ala735GlnfsTer34	frameshift	Exon 18 of 25	NP_001269353.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift	Exon 29 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.2326_2327delGC	p.Ala776GlnfsTer34	frameshift	Exon 18 of 25	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.2203_2204delGC	p.Ala735GlnfsTer34	frameshift	Exon 18 of 25	ENSP00000438292.1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5470 AN: 152158 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0455

GnomAD2 exomes AF: 0.0432 AC: 10760 AN: 249188 AF XY: 0.0459

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0487 AC: 71145 AN: 1460906 Hom.: 1920 AF XY: 0.0496 AC XY: 36049 AN XY: 726772

African (AFR) AF: 0.00921 AC: 308 AN: 33456

American (AMR) AF: 0.0293 AC: 1309 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 1631 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0687 AC: 5921 AN: 86186

European-Finnish (FIN) AF: 0.0317 AC: 1695 AN: 53398

Middle Eastern (MID) AF: 0.0846 AC: 432 AN: 5106

European-Non Finnish (NFE) AF: 0.0513 AC: 57032 AN: 1111914

Other (OTH) AF: 0.0466 AC: 2812 AN: 60292

GnomAD4 genome AF: 0.0359 AC: 5468 AN: 152276 Hom.: 134 Cov.: 33 AF XY: 0.0351 AC XY: 2617 AN XY: 74454

African (AFR) AF: 0.0106 AC: 441 AN: 41556

American (AMR) AF: 0.0358 AC: 547 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3468

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0633 AC: 305 AN: 4818

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0514 AC: 3495 AN: 68026

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

Alfa AF: 0.0458 Hom.: 33

Bravo AF: 0.0346

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.0537

EpiControl AF: 0.0567

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	1	-	Otitis media (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=157/43	disease causing (fs/PTC)

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: rs144686314; hg19: chr12-9016562; COSMIC: COSV55288502; COSMIC: COSV55288502;