rs61749078

Positions:

• chr12-8861175-C-T

Variant summary

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

The NM_144670.6(A2ML1):​c.3380C>T​(p.Ser1127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,996 control chromosomes in the GnomAD database, including 85 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.471

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031675994).
• BP6: Variant 12-8861175-C-T is Benign according to our data. Variant chr12-8861175-C-T is described in ClinVar as [Benign]. Clinvar id is 241904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8861175-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1906/152110) while in subpopulation AFR AF= 0.0432 (1791/41468). AF 95% confidence interval is 0.0415. There are 38 homozygotes in gnomad4. There are 895 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1906 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.3380C>T	p.Ser1127Leu	missense_variant	28/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.3380C>T	p.Ser1127Leu	missense_variant	28/36	1	NM_144670.6	ENSP00000299698	P1
	ENST00000631830.1	n.322-2899G>A		intron_variant, non_coding_transcript_variant		3
A2ML1	ENST00000541459.5	c.2030C>T	p.Ser677Leu	missense_variant	17/25	2		ENSP00000443174
A2ML1	ENST00000539547.5	c.1907C>T	p.Ser636Leu	missense_variant	17/25	2		ENSP00000438292

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1888 AN: 151992 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00329 AC: 820 AN: 249530 Hom.: 14 AF XY: 0.00256 AC XY: 346 AN XY: 135374

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00135 AC: 1979 AN: 1461886 Hom.: 47 Cov.: 32 AF XY: 0.00117 AC XY: 848 AN XY: 727242

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0125 AC: 1906 AN: 152110 Hom.: 38 Cov.: 32 AF XY: 0.0120 AC XY: 895 AN XY: 74370

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00210 Hom.: 19

Bravo AF: 0.0149

ESP6500AA AF: 0.0400 AC: 157

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00406 AC: 491

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2019	Variant summary: A2ML1 c.3380C>T (p.Ser1127Leu) results in a non-conservative amino acid change located in the Alpha-macroglobulin-like, TED domain (IPR011626) of 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 0.0033 in 249530 control chromosomes, predominantly at a frequency of 0.044 within the African or African-American subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11000-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.3380C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;D;D
REVEL	Benign	0.087
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.31
MVP		0.14
MPC		0.32
ClinPred		0.040	T
GERP RS		3.6
Varity_R		0.40
gMVP		0.29

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: rs61749078; hg19: chr12-9013771;