chr12-8841389-T-C

Variant names:

• chr12-8841389-T-C
• rs61744222
• NM_144670.6:c.1101T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144670.6(A2ML1):​c.1101T>C​(p.Asp367Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,070 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (177 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.489
• Publications: 1 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-8841389-T-C is Benign according to our data. Variant chr12-8841389-T-C is described in ClinVar as Benign. ClinVar VariationId is 413815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 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.1101T>C	p.Asp367Asp	synonymous	Exon 11 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.1101T>C	p.Asp367Asp	synonymous	Exon 11 of 36	ENSP00000299698.7	A8K2U0-1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4002 AN: 152158 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00671 AC: 1674 AN: 249470 AF XY: 0.00465

Gnomad AFR exome AF: 0.0927

Gnomad AMR exome AF: 0.00484

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00272 AC: 3970 AN: 1461794 Hom.: 177 Cov.: 30 AF XY: 0.00227 AC XY: 1649 AN XY: 727202

African (AFR) AF: 0.0930 AC: 3109 AN: 33422

American (AMR) AF: 0.00579 AC: 259 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1111994

Other (OTH) AF: 0.00573 AC: 346 AN: 60386

GnomAD4 genome AF: 0.0263 AC: 4006 AN: 152276 Hom.: 177 Cov.: 32 AF XY: 0.0254 AC XY: 1892 AN XY: 74472

African (AFR) AF: 0.0909 AC: 3774 AN: 41536

American (AMR) AF: 0.0114 AC: 175 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00846 Hom.: 39

Bravo AF: 0.0298

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.5
DANN	Benign	0.86
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61744222; hg19: chr12-8993985;