rs11047493

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144670.6(A2ML1):c.463-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,613,992 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 178 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 170 hom. )

Consequence

A2ML1
NM_144670.6 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001460

Clinical Significance

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

Conservation

PhyloP100: 0.0400

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 12-8834653-C-G is Benign according to our data. Variant chr12-8834653-C-G is described in ClinVar as [Benign]. Clinvar id is 413819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8834653-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 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.463-9C>G		splice_polypyrimidine_tract_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.463-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
A2ML1	ENST00000537546.1 linkuse as main transcript	n.287-9C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0264

AC:

4014

AN:

152220

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0913

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00669

AC:

1668

AN:

249300

Hom.:

AF XY:

0.00463

AC XY:

626

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.0925

Gnomad AMR exome

AF:

0.00473

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00275

AC:

4016

AN:

1461654

Hom.:

170

Cov.:

AF XY:

0.00231

AC XY:

1681

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0932

Gnomad4 AMR exome

AF:

0.00582

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.00566

GnomAD4 genome

AF:

0.0264

AC:

4018

AN:

152338

Hom.:

178

Cov.:

AF XY:

0.0256

AC XY:

1907

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0911

Gnomad4 AMR

AF:

0.0113

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00691

Hom.:

Bravo

AF:

0.0301

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 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 provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.463-9C>G variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 981/120728 control chromosomes (46 homozygotes) from ExAC, predominantly observed in the African subpopulation at a frequency of 0.090937 (891/9798). This frequency is about 22734 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a common benign polymorphism found primarily in the populations of African origin. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.1

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.050

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