rs7308106

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144670.6(A2ML1):c.1275A>G(p.Val425Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,613,954 control chromosomes in the GnomAD database, including 7,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V425V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 494 hom., cov: 32)

Exomes 𝑓: 0.091 ( 6804 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.208

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Orphanet, ClinGen, Genomics England PanelApp
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-8843160-A-G is Benign according to our data. Variant chr12-8843160-A-G is described in ClinVar as Benign. ClinVar VariationId is 384677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.208 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144670.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.1275A>G	p.Val425Val	synonymous	Exon 12 of 36	NP_653271.3	A8K2U0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.1275A>G	p.Val425Val	synonymous	Exon 12 of 36	ENSP00000299698.7	A8K2U0-1
	A2ML1	ENST00000541459.5	TSL:2	c.-76A>G		upstream_gene	N/A	ENSP00000443174.1	H0YGG5

Frequencies

GnomAD3 genomes

AF:

0.0660

AC:

10048

AN:

152176

Hom.:

494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0739

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0547

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0994

Gnomad OTH

AF:

0.0847

GnomAD2 exomes

AF:

0.0711

AC:

17747

AN:

249524

AF XY:

0.0716

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0565

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0580

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0921

GnomAD4 exome

AF:

0.0906

AC:

132401

AN:

1461660

Hom.:

6804

Cov.:

AF XY:

0.0894

AC XY:

65034

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0145

AC:

484

AN:

33480

American (AMR)

AF:

0.0582

AC:

2601

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3663

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0329

AC:

2837

AN:

86248

European-Finnish (FIN)

AF:

0.0603

AC:

3221

AN:

53420

Middle Eastern (MID)

AF:

0.116

AC:

669

AN:

5766

European-Non Finnish (NFE)

AF:

0.102

AC:

113608

AN:

1111808

Other (OTH)

AF:

0.0880

AC:

5312

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

5917

11835

17752

23670

29587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4014

8028

12042

16056

20070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0660

AC:

10044

AN:

152294

Hom.:

494

Cov.:

AF XY:

0.0626

AC XY:

4663

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0179

AC:

743

AN:

41572

American (AMR)

AF:

0.0738

AC:

1128

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

483

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0251

AC:

121

AN:

4828

European-Finnish (FIN)

AF:

0.0547

AC:

581

AN:

10616

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0995

AC:

6766

AN:

68014

Other (OTH)

AF:

0.0838

AC:

177

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

481

962

1442

1923

2404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0892

Hom.:

1530

Bravo

AF:

0.0650

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0984

EpiControl

AF:

0.101

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.4

(source)

DANN

Benign

0.66

PhyloP100

-0.21

PromoterAI

0.0066

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over