rs142794811

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId 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.

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.3108-3dupT		splice_acceptor intron	N/A	NP_653271.3
	A2ML1	NM_001282424.3		c.1635-3dupT		splice_acceptor intron	N/A	NP_001269353.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.3108-4_3108-3insT		splice_region intron	N/A	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.1758-4_1758-3insT		splice_region intron	N/A	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.1635-4_1635-3insT		splice_region intron	N/A	ENSP00000438292.1

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

GnomAD2 exomes AF: 0.0255 AC: 6349 AN: 249196 AF XY: 0.0209

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 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

African (AFR) AF: 0.000926 AC: 31 AN: 33464

American (AMR) AF: 0.112 AC: 4982 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26108

East Asian (EAS) AF: 0.0945 AC: 3750 AN: 39696

South Asian (SAS) AF: 0.00361 AC: 311 AN: 86216

European-Finnish (FIN) AF: 0.00455 AC: 243 AN: 53406

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00191 AC: 2121 AN: 1111870

Other (OTH) AF: 0.00772 AC: 466 AN: 60380

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

African (AFR) AF: 0.00181 AC: 75 AN: 41526

American (AMR) AF: 0.0426 AC: 651 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0856 AC: 443 AN: 5178

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4826

European-Finnish (FIN) AF: 0.00585 AC: 62 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Otitis media, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs142794811; hg19: chr12-9010538; COSMIC: COSV55289604; COSMIC: COSV55289604;