rs1060500994

Variant names:

• chr12-8855571-A-C
• NM_144670.6:c.2827A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-8855571-A-C
• chr12-8855571-A-G

Variant summary

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

The NM_144670.6(A2ML1):​c.2827A>C​(p.Lys943Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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]

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=0.22250214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.2827A>C	p.Lys943Gln	missense_variant	Exon 23 of 36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.2827A>C	p.Lys943Gln	missense_variant	Exon 23 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5	c.1477A>C	p.Lys493Gln	missense_variant	Exon 12 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5	c.1354A>C	p.Lys452Gln	missense_variant	Exon 12 of 25	2		ENSP00000438292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.033
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.57	P;.;.
Vest4		0.36
MutPred		0.62		Loss of ubiquitination at K943 (P = 0.0118);.;.;
MVP		0.092
MPC		0.16
ClinPred		0.55	D
GERP RS		2.3
Varity_R		0.080
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-9008167;