Variant 12-8822714-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_144670.6(A2ML1):c.62+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

A2ML1
NM_144670.6 splice_donor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.905

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-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

A2ML1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.021076746 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.62+1G>C		splice_donor_variant		ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.62+1G>C		splice_donor_variant		1	NM_144670.6	P1	A8K2U0-1
A2ML1-AS1	ENST00000537288.1 linkuse as main transcript	n.286+7948C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249522

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in A2ML1 cause disease. This variant has not been reported in the literature in individuals with A2ML1-related conditions. This variant is present in population databases (rs200764174, ExAC 0.01%). This sequence change affects a donor splice site in intron 1 of the A2ML1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.93

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.74

MutationTaster

Benign

1.0

GERP RS

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: -1

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