chr12-8823319-A-T

Position:

• chr12-8823319-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000299698.12(A2ML1):​c.200A>T​(p.Glu67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,614,182 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E67E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (21 hom.)
• Consequence: A2ML1 ENST00000299698.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031451285).
• BP6: Variant 12-8823319-A-T is Benign according to our data. Variant chr12-8823319-A-T is described in ClinVar as [Benign]. Clinvar id is 241887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00076 (1111/1461880) while in subpopulation AMR AF= 0.024 (1075/44722). AF 95% confidence interval is 0.0228. There are 21 homozygotes in gnomad4_exome. There are 470 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.200A>T	p.Glu67Val	missense_variant	2/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.200A>T	p.Glu67Val	missense_variant	2/36	1	NM_144670.6	ENSP00000299698	P1
A2ML1-AS1	ENST00000537288.1	n.286+7343T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00361 AC: 901 AN: 249528 Hom.: 18 AF XY: 0.00275 AC XY: 372 AN XY: 135376

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.000760 AC: 1111 AN: 1461880 Hom.: 21 Cov.: 31 AF XY: 0.000646 AC XY: 470 AN XY: 727244

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0240

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: 0.00000450

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000282 Hom.: 1

Bravo AF: 0.00237

ExAC AF: 0.00298 AC: 360

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2019	Variant summary: A2ML1 c.200A>T (p.Glu67Val) 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 0.0036 in 249528 control chromosomes, predominantly at a frequency of 0.026 within the Latino subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6500-folds over 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 Latino origin. To our knowledge, no occurrence of c.200A>T 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.12
Sift	Uncertain	0.017	D
Sift4G	Benign	0.13	T
Polyphen		0.11	B
Vest4		0.26
MVP		0.12
MPC		0.20
ClinPred		0.032	T
GERP RS		3.1
Varity_R		0.30
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs190479708; hg19: chr12-8975915;