chr12-8863966-GGC-G

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

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]

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 id is 413822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8863966-GGC-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift_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.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.2326_2327delGC	p.Ala776GlnfsTer34	frameshift_variant	Exon 18 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.2203_2204delGC	p.Ala735GlnfsTer34	frameshift_variant	Exon 18 of 25	2		ENSP00000438292.1
ENSG00000282022	ENST00000631830.1	n.322-5692_322-5691delGC		intron_variant	Intron 1 of 1	3

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

Gnomad4 AFR exome AF: 0.00921 AC: 308 AN: 33456

Gnomad4 AMR exome AF: 0.0293 AC: 1309 AN: 44722

Gnomad4 ASJ exome AF: 0.0624 AC: 1631 AN: 26132

Gnomad4 EAS exome AF: 0.000126 AC: 5 AN: 39700

Gnomad4 SAS exome AF: 0.0687 AC: 5921 AN: 86186

Gnomad4 FIN exome AF: 0.0317 AC: 1695 AN: 53398

Gnomad4 NFE exome AF: 0.0513 AC: 57032 AN: 1111914

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0106 AC: 0.0106122 AN: 0.0106122

Gnomad4 AMR AF: 0.0358 AC: 0.0357516 AN: 0.0357516

Gnomad4 ASJ AF: 0.0620 AC: 0.0619954 AN: 0.0619954

Gnomad4 EAS AF: 0.000966 AC: 0.000965624 AN: 0.000965624

Gnomad4 SAS AF: 0.0633 AC: 0.0633043 AN: 0.0633043

Gnomad4 FIN AF: 0.0302 AC: 0.0301545 AN: 0.0301545

Gnomad4 NFE AF: 0.0514 AC: 0.0513774 AN: 0.0513774

Gnomad4 OTH AF: 0.0450 AC: 0.0449811 AN: 0.0449811

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

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24896146) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otitis media Uncertain:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Benign:1

Aug 12, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: A2ML1 c.3676_3677delGC (p.Ala1226GlnfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, the variant allele was found at a frequency of 0.043 in 249188 control chromosomes, predominantly at a frequency of 0.068 within the South Asian subpopulation in the gnomAD database, including 87 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17000-folds over the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

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