12-8855578-AT-GC

Variant names:

• chr12-8855578-AT-GC
• NM_144670.6:c.2834_2835delATinsGC
• A2ML1 p.Tyr945Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_144670.6(A2ML1):​c.2834_2835delATinsGC​(p.Tyr945Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y945F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.2834_2835delATinsGC	p.Tyr945Cys	missense	N/A	NP_653271.3	A8K2U0-1
	A2ML1	NM_001282424.3		c.1361_1362delATinsGC	p.Tyr454Cys	missense	N/A	NP_001269353.2	A8K2U0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.2834_2835delATinsGC	p.Tyr945Cys	missense	N/A	ENSP00000299698.7	A8K2U0-1
	A2ML1	ENST00000541459.5	TSL:2	c.1484_1485delATinsGC	p.Tyr495Cys	missense	N/A	ENSP00000443174.1	H0YGG5
	A2ML1	ENST00000539547.5	TSL:2	c.1361_1362delATinsGC	p.Tyr454Cys	missense	N/A	ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.084

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-9008174;