chr12-8851801-C-T

Variant names:

• chr12-8851801-C-T
• rs61741216
• NM_144670.6:c.2252C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144670.6(A2ML1):​c.2252C>T​(p.Ala751Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,050 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A751T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (27 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.289
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037553012).
• BP6: Variant 12-8851801-C-T is Benign according to our data. Variant chr12-8851801-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00904 (1376/152238) while in subpopulation AFR AF = 0.031 (1286/41530). AF 95% confidence interval is 0.0296. There are 26 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1376 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.2252C>T	p.Ala751Val	missense	Exon 19 of 36	NP_653271.3
	A2ML1	NM_001282424.3		c.779C>T	p.Ala260Val	missense	Exon 8 of 25	NP_001269353.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.2252C>T	p.Ala751Val	missense	Exon 19 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.902C>T	p.Ala301Val	missense	Exon 8 of 25	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.779C>T	p.Ala260Val	missense	Exon 8 of 25	ENSP00000438292.1

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1373 AN: 152120 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00223 AC: 555 AN: 249426 AF XY: 0.00173

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000950 AC: 1389 AN: 1461812 Hom.: 27 Cov.: 30 AF XY: 0.000846 AC XY: 615 AN XY: 727194

African (AFR) AF: 0.0317 AC: 1060 AN: 33478

American (AMR) AF: 0.00179 AC: 80 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5732

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1111996

Other (OTH) AF: 0.00222 AC: 134 AN: 60390

GnomAD4 genome AF: 0.00904 AC: 1376 AN: 152238 Hom.: 26 Cov.: 32 AF XY: 0.00880 AC XY: 655 AN XY: 74450

African (AFR) AF: 0.0310 AC: 1286 AN: 41530

American (AMR) AF: 0.00432 AC: 66 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00319 Hom.: 21

Bravo AF: 0.0105

ESP6500AA AF: 0.0288 AC: 119

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00272 AC: 329

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N
PhyloP100		-0.29
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.096
Sift	Benign	0.082	T
Sift4G	Uncertain	0.036	D
Polyphen		0.029	B
Vest4		0.047
MVP		0.040
MPC		0.11
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.22
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61741216; hg19: chr12-9004397; COSMIC: COSV99075348; COSMIC: COSV99075348;