rs79149293

Positions:

• chr12-8823277-C-G
• chr12-8823277-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144670.6(A2ML1):​c.158C>G​(p.Thr53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,614,110 control chromosomes in the GnomAD database, including 13 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. T53M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26

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-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018659174).
• BP6: Variant 12-8823277-C-G is Benign according to our data. Variant chr12-8823277-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 413807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8823277-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.158C>G	p.Thr53Arg	missense_variant	2/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.158C>G	p.Thr53Arg	missense_variant	2/36	1	NM_144670.6	P1
A2ML1-AS1	ENST00000537288.1	n.286+7385G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00214 AC: 535 AN: 249546 Hom.: 1 AF XY: 0.00217 AC XY: 294 AN XY: 135394

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.000835

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00361 AC: 5274 AN: 1461850 Hom.: 13 Cov.: 31 AF XY: 0.00357 AC XY: 2599 AN XY: 727238

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74456

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00271 Hom.: 1

Bravo AF: 0.00185

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00389 AC: 32

ExAC AF: 0.00237 AC: 287

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2019

Variant summary: A2ML1 c.158C>G (p.Thr53Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 249546 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 850 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.158C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
Eigen	Benign	0.040
Eigen_PC	Benign	0.0053
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.25	T
Sift4G	Benign	0.49	T
Polyphen		0.99	D
Vest4		0.65
MVP		0.076
MPC		0.50
ClinPred		0.023	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79149293; hg19: chr12-8975873; COSMIC: COSV105169969; COSMIC: COSV105169969;