12-8823305-C-T

Position:

chr12-8823305-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_144670.6(A2ML1):c.186C>T(p.Thr62Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 1,613,902 control chromosomes in the GnomAD database, including 5,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 418 hom., cov: 32)

Exomes 𝑓: 0.061 ( 4807 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.259

Variant links:

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 links:

A2ML1 (HGNC:):

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 12-8823305-C-T is Benign according to our data. Variant chr12-8823305-C-T is described in ClinVar as [Benign]. Clinvar id is 384687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8823305-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.259 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.186C>T	p.Thr62Thr	synonymous_variant	2/36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.186C>T	p.Thr62Thr	synonymous_variant	2/36	1	NM_144670.6	ENSP00000299698.7		A8K2U0-1
A2ML1-AS1	ENST00000537288.1 linkuse as main transcript	n.286+7357G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0569

AC:

8649

AN:

151974

Hom.:

417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.0575

Gnomad ASJ

AF:

0.0677

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.0532

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0438

Gnomad OTH

AF:

0.0546

GnomAD3 exomes

AF:

0.0879

AC:

21924

AN:

249524

Hom.:

1651

AF XY:

0.0942

AC XY:

12757

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.0382

Gnomad AMR exome

AF:

0.0782

Gnomad ASJ exome

AF:

0.0650

Gnomad EAS exome

AF:

0.203

Gnomad SAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.0613

Gnomad NFE exome

AF:

0.0460

Gnomad OTH exome

AF:

0.0747

GnomAD4 exome

AF:

0.0609

AC:

88978

AN:

1461810

Hom.:

4807

Cov.:

AF XY:

0.0659

AC XY:

47920

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0350

Gnomad4 AMR exome

AF:

0.0747

Gnomad4 ASJ exome

AF:

0.0678

Gnomad4 EAS exome

AF:

0.189

Gnomad4 SAS exome

AF:

0.234

Gnomad4 FIN exome

AF:

0.0622

Gnomad4 NFE exome

AF:

0.0423

Gnomad4 OTH exome

AF:

0.0699

GnomAD4 genome

AF:

0.0569

AC:

8658

AN:

152092

Hom.:

418

Cov.:

AF XY:

0.0628

AC XY:

4668

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0358

Gnomad4 AMR

AF:

0.0579

Gnomad4 ASJ

AF:

0.0677

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.256

Gnomad4 FIN

AF:

0.0532

Gnomad4 NFE

AF:

0.0439

Gnomad4 OTH

AF:

0.0573

Alfa

AF:

0.0476

Hom.:

169

Bravo

AF:

0.0538

Asia WGS

AF:

0.187

AC:

651

AN:

3478

EpiCase

AF:

0.0482

EpiControl

AF:

0.0468

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The A2ML1 c.186C>T (p.Thr62Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 10767/120732 control chromosomes (858 homozygotes) from ExAC at a frequency of 0.089181, which is approximately 22295 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus this variant is a common benign polymorphism. It has also been published as a benign SNP in literature (Justino_2014/2015). In addition, one clinical diagnostic laboratory (via ClinVar) has classified this variant as benign. Taken together, this variant is classified as benign. -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

6.1

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over