NM_144670.6:c.3550A>C

Variant names:

• chr12-8863841-A-C
• NM_144670.6:c.3550A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144670.6(A2ML1):​c.3550A>C​(p.Ser1184Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155

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]

ENSG00000282022 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070925474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3550A>C	p.Ser1184Arg	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.3550A>C	p.Ser1184Arg	missense_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.2200A>C	p.Ser734Arg	missense_variant	Exon 18 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.2077A>C	p.Ser693Arg	missense_variant	Exon 18 of 25	2		ENSP00000438292.1
ENSG00000282022	ENST00000631830.1	n.322-5565T>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.6
DANN	Benign	0.87
DEOGEN2	Benign	0.0072	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.024	B;.;.
Vest4		0.18
MutPred		0.46		Loss of glycosylation at S1184 (P = 0.0249);.;.;
MVP		0.014
MPC		0.13
ClinPred		0.064	T
GERP RS		-3.3
Varity_R		0.039
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-9016437;