dbSNP rs17792974: A2ML1:p.Thr62Thr (chr12-8823305-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

10 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 links:

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

A2ML1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 384687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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.186C>T	p.Thr62Thr	synonymous	Exon 2 of 36	NP_653271.3	A8K2U0-1
	A2ML1-AS1	NR_046715.1		n.645+7357G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.186C>T	p.Thr62Thr	synonymous	Exon 2 of 36	ENSP00000299698.7	A8K2U0-1
A2ML1-AS1	ENST00000537288.1	TSL:3	n.286+7357G>A		intron	N/A
A2ML1	ENST00000537546.1	TSL:4	n.-208C>T		upstream_gene	N/A

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

GnomAD2 exomes

AF:

0.0879

AC:

21924

AN:

249524

AF XY:

0.0942

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 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

African (AFR)

AF:

0.0350

AC:

1173

AN:

33476

American (AMR)

AF:

0.0747

AC:

3341

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0678

AC:

1773

AN:

26132

East Asian (EAS)

AF:

0.189

AC:

7490

AN:

39694

South Asian (SAS)

AF:

0.234

AC:

20218

AN:

86236

European-Finnish (FIN)

AF:

0.0622

AC:

3322

AN:

53418

Middle Eastern (MID)

AF:

0.0794

AC:

458

AN:

5768

European-Non Finnish (NFE)

AF:

0.0423

AC:

46983

AN:

1111968

Other (OTH)

AF:

0.0699

AC:

4220

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4206

8411

12617

16822

21028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1984

3968

5952

7936

9920

<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:

0.0569

AC:

8658

AN:

152092

Hom.:

418

Cov.:

AF XY:

0.0628

AC XY:

4668

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0358

AC:

1483

AN:

41468

American (AMR)

AF:

0.0579

AC:

884

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0677

AC:

235

AN:

3472

East Asian (EAS)

AF:

0.201

AC:

1038

AN:

5168

South Asian (SAS)

AF:

0.256

AC:

1232

AN:

4816

European-Finnish (FIN)

AF:

0.0532

AC:

564

AN:

10594

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0439

AC:

2982

AN:

67996

Other (OTH)

AF:

0.0573

AC:

121

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

397

794

1190

1587

1984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0463

Hom.:

255

Bravo

AF:

0.0538

Asia WGS

AF:

0.187

AC:

651

AN:

3478

EpiCase

AF:

0.0482

EpiControl

AF:

0.0468

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

-0.42

CADD

Benign

6.1

(source)

DANN

Benign

0.86

PhyloP100

-0.26

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

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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