12-8860888-T-C

Variant names:

• chr12-8860888-T-C
• rs61736726
• NM_144670.6:c.3272T>C

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.3272T>C​(p.Val1091Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,614,078 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1091G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.24
• Publications: 8 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

ENSG00000282022 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045797527).
• BP6: Variant 12-8860888-T-C is Benign according to our data. Variant chr12-8860888-T-C is described in ClinVar as Benign. ClinVar VariationId is 241902.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 = 0.0121 (1845/152204) while in subpopulation AFR AF = 0.0425 (1763/41500). AF 95% confidence interval is 0.0408. There are 45 homozygotes in GnomAd4. There are 836 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1845 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.3272T>C	p.Val1091Ala	missense	Exon 27 of 36	NP_653271.3
	A2ML1	NM_001282424.3		c.1799T>C	p.Val600Ala	missense	Exon 16 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.3272T>C	p.Val1091Ala	missense	Exon 27 of 36	ENSP00000299698.7
	A2ML1	ENST00000541459.5	TSL:2	c.1922T>C	p.Val641Ala	missense	Exon 16 of 25	ENSP00000443174.1
	A2ML1	ENST00000539547.5	TSL:2	c.1799T>C	p.Val600Ala	missense	Exon 16 of 25	ENSP00000438292.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1838 AN: 152086 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

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: 0.0000588

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00291 AC: 725 AN: 249556 AF XY: 0.00232

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00123 AC: 1793 AN: 1461874 Hom.: 32 Cov.: 31 AF XY: 0.00113 AC XY: 819 AN XY: 727238

African (AFR) AF: 0.0427 AC: 1431 AN: 33476

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1112006

Other (OTH) AF: 0.00270 AC: 163 AN: 60390

GnomAD4 genome AF: 0.0121 AC: 1845 AN: 152204 Hom.: 45 Cov.: 32 AF XY: 0.0112 AC XY: 836 AN XY: 74426

African (AFR) AF: 0.0425 AC: 1763 AN: 41500

American (AMR) AF: 0.00413 AC: 63 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00379 Hom.: 25

Bravo AF: 0.0140

ESP6500AA AF: 0.0401 AC: 172

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00360 AC: 436

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Aug 19, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: A2ML1 c.3272T>C (p.Val1091Ala) results in a non-conservative amino acid change located in the alpha-2-macroglobulin, TED domain (IPR041813) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 249556 control chromosomes, predominantly at a frequency of 0.042 within the African or African-American subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10500 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 African or African-American origin. To our knowledge, no occurrence of c.3272T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.2
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.18
MPC		0.54
ClinPred		0.029	T
GERP RS		4.0
Varity_R		0.36
gMVP		0.23
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs61736726; hg19: chr12-9013484;