NM_144670.6:c.621T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_144670.6(A2ML1):c.621T>C(p.Gly207Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,614,176 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 36 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0700

Publications

4 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=-0.64).

BP6

Variant 12-8835644-T-C is Benign according to our data. Variant chr12-8835644-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00235 (3438/1461854) while in subpopulation MID AF = 0.0168 (97/5766). AF 95% confidence interval is 0.0151. There are 36 homozygotes in GnomAdExome4. There are 2051 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 395 AD gene.

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.621T>C	p.Gly207Gly	synonymous	Exon 6 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.621T>C	p.Gly207Gly	synonymous	Exon 6 of 36	ENSP00000299698.7	A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

397

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00376

AC:

937

AN:

249434

AF XY:

0.00449

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00413

GnomAD4 exome

AF:

0.00235

AC:

3438

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2051

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00237

AC:

106

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0158

AC:

1365

AN:

86258

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00127

AC:

1409

AN:

1111992

Other (OTH)

AF:

0.00326

AC:

197

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

192

384

576

768

960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00259

AC:

395

AN:

152322

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41572

American (AMR)

AF:

0.00242

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0153

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00191

AC:

130

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00212

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00326

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

A2ML1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.0

(source)

DANN

Benign

0.72

PhyloP100

-0.070

Mutation Taster

=100/0

polymorphism

(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