rs61745125

Positions:

• chr12-8858090-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_144670.6(A2ML1):​c.3252C>T​(p.His1084=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,614,110 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (44 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.802

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-8858090-C-T is Benign according to our data. Variant chr12-8858090-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8858090-C-T is described in Lovd as [Likely_benign]. Variant chr12-8858090-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.802 with no splicing effect.
• BS2: High AC in GnomAd4 at 716 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.3252C>T	p.His1084=	synonymous_variant	26/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.3252C>T	p.His1084=	synonymous_variant	26/36	1	NM_144670.6	P1
A2ML1	ENST00000541459.5	c.1902C>T	p.His634=	synonymous_variant	15/25	2
A2ML1	ENST00000539547.5	c.1779C>T	p.His593=	synonymous_variant	15/25	2

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 716 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00495 AC: 1233 AN: 249320 Hom.: 5 AF XY: 0.00479 AC XY: 648 AN XY: 135276

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00536 AC: 7839 AN: 1461810 Hom.: 44 Cov.: 32 AF XY: 0.00524 AC XY: 3811 AN XY: 727196

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.00563

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00470 AC: 716 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00520 AC XY: 387 AN XY: 74472

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.00623

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00514 Hom.: 0

Bravo AF: 0.00307

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	A2ML1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2016	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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

A2ML1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.0
DANN	Benign	0.47

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: rs61745125; hg19: chr12-9010686;