rs61744220

Positions:

• chr12-8841397-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144670.6(A2ML1):​c.1109T>C​(p.Phe370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,056 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (177 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0210

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014653802).
• BP6: Variant 12-8841397-T-C is Benign according to our data. Variant chr12-8841397-T-C is described in ClinVar as [Benign]. Clinvar id is 120251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8841397-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6	c.1109T>C	p.Phe370Ser	missense_variant	11/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12	c.1109T>C	p.Phe370Ser	missense_variant	11/36	1	NM_144670.6	P1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4003 AN: 152116 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00670 AC: 1671 AN: 249494 Hom.: 86 AF XY: 0.00464 AC XY: 628 AN XY: 135366

Gnomad AFR exome AF: 0.0927

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00271 AC: 3965 AN: 1461822 Hom.: 177 Cov.: 31 AF XY: 0.00226 AC XY: 1644 AN XY: 727214

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.0263 AC: 4007 AN: 152234 Hom.: 177 Cov.: 32 AF XY: 0.0254 AC XY: 1892 AN XY: 74454

Gnomad4 AFR AF: 0.0909

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00430 Hom.: 44

Bravo AF: 0.0298

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0808 AC: 308

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00803 AC: 970

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Dec 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The A2ML1 c.1109T>C (p.Phe370Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 967/120708 control chromosomes (48 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.089778 (880/9802). This frequency is about 22444 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a benign common polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory (via ClinVar) has classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.032
Sift	Benign	0.51	T
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.19
MVP		0.048
MPC		0.19
ClinPred		0.0014	T
GERP RS		2.8
Varity_R		0.077
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs61744220; hg19: chr12-8993993;