rs142794811

Variant names:

• chr12-8857942-G-GT
• rs142794811
• NM_144670.6:c.3108-3dupT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_144670.6(A2ML1):​c.3108-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,613,820 control chromosomes in the GnomAD database, including 617 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (49 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (568 hom.)
• Consequence: A2ML1 NM_144670.6 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.517

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

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035967927 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of 0 (no position change), new splice context is: ttcctctttacccatgttAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 12-8857942-G-GT is Benign according to our data. Variant chr12-8857942-G-GT is described in ClinVar as [Benign]. Clinvar id is 252784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3108-3dupT		splice_acceptor_variant, intron_variant	Intron 25 of 35	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.3108-4_3108-3insT		splice_region_variant, intron_variant	Intron 25 of 35	1	NM_144670.6	ENSP00000299698.7

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1428 AN: 152116 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0850

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0255 AC: 6349 AN: 249196 Hom.: 409 AF XY: 0.0209 AC XY: 2820 AN XY: 135230

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.0943

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.00525

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.00819 AC: 11964 AN: 1461586 Hom.: 568 Cov.: 30 AF XY: 0.00766 AC XY: 5569 AN XY: 727094

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0945

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.00191

Gnomad4 OTH exome AF: 0.00772

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152234 Hom.: 49 Cov.: 31 AF XY: 0.0105 AC XY: 782 AN XY: 74428

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.0426

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0856

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00502 Hom.: 6

Bravo AF: 0.0155

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 19, 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.3108-3dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.024 in 280586 control chromosomes in the gnomAD database, including 417 homozygotes. The observed variant frequency is approximately 5937-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 benign. Three ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jul 14, 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. -

Nov 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otitis media, susceptibility to Benign:1

Nov 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142794811; hg19: chr12-9010538;