rs61744220

Variant names:

• chr12-8841397-T-C
• rs61744220
• NM_144670.6:c.1109T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:6 O:1
• Conservation: PhyloP100: -0.0210
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 120251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

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.1109T>C	p.Phe370Ser	missense	Exon 11 of 36	NP_653271.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.1109T>C	p.Phe370Ser	missense	Exon 11 of 36	ENSP00000299698.7

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

GnomAD2 exomes AF: 0.00670 AC: 1671 AN: 249494 AF XY: 0.00464

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 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

African (AFR) AF: 0.0933 AC: 3119 AN: 33438

American (AMR) AF: 0.00577 AC: 258 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000165 AC: 184 AN: 1112004

Other (OTH) AF: 0.00575 AC: 347 AN: 60388

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

African (AFR) AF: 0.0909 AC: 3776 AN: 41522

American (AMR) AF: 0.0115 AC: 175 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68030

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00893 Hom.: 121

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.021
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
Mutation Taster		=97/3	polymorphism (auto)

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: rs61744220; hg19: chr12-8993993;