rs73037000

Positions:

chr12-8834689-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_144670.6(A2ML1):c.483+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,614,042 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 75 hom. )

Consequence

A2ML1
NM_144670.6 splice_region, intron

Scores

Splicing: ADA: 0.00002828

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.168

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 12-8834689-G-A is Benign according to our data. Variant chr12-8834689-G-A is described in ClinVar as [Benign]. Clinvar id is 241910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8834689-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 930 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.483+7G>A		splice_region_variant, intron_variant		ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.483+7G>A		splice_region_variant, intron_variant		1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
A2ML1	ENST00000537546.1 linkuse as main transcript	n.314G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes

AF:

0.00611

AC:

930

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00805

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00655

AC:

1634

AN:

249462

Hom.:

AF XY:

0.00649

AC XY:

879

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00128

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.00958

Gnomad OTH exome

AF:

0.00578

GnomAD4 exome

AF:

0.00788

AC:

11516

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

5548

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00336

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00151

Gnomad4 FIN exome

AF:

0.0158

Gnomad4 NFE exome

AF:

0.00899

Gnomad4 OTH exome

AF:

0.00565

GnomAD4 genome

AF:

0.00611

AC:

930

AN:

152300

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

463

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0194

Gnomad4 NFE

AF:

0.00806

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00708

Hom.:

Bravo

AF:

0.00552

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00806

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.483+7G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 838/120722 control chromosomes (9 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.01648 (109/6614). This frequency is about 4120 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	A2ML1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.5

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.0

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

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