NM_144670.6:c.3686A>C

Variant names:

• chr12-8863977-A-C
• rs10219561
• NM_144670.6:c.3686A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144670.6(A2ML1):​c.3686A>C​(p.His1229Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1229R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 21 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: Genomics England PanelApp, ClinGen, Orphanet

ENSG00000282022 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25638023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3686A>C	p.His1229Pro	missense_variant	Exon 29 of 36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.3686A>C	p.His1229Pro	missense_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.2336A>C	p.His779Pro	missense_variant	Exon 18 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.2213A>C	p.His738Pro	missense_variant	Exon 18 of 25	2		ENSP00000438292.1
ENSG00000282022	ENST00000631830.1	n.322-5701T>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.0095	T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.29	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.
PhyloP100		1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.0020	B;.;.
Vest4		0.19
MutPred		0.76		Loss of MoRF binding (P = 0.082);.;.;
MVP		0.030
MPC		0.17
ClinPred		0.21	T
GERP RS		-1.1
Varity_R		0.26
gMVP		0.74
Mutation Taster		=98/2	polymorphism

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: rs10219561; hg19: chr12-9016573;