rs7315591

Variant names:

• chr12-8874437-A-G
• rs7315591
• NM_144670.6:c.4234A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-8874437-A-G
• chr12-8874437-A-T

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.4234A>G​(p.Thr1412Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,613,884 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. T1412S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (158 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (155 hom.)
• Consequence: A2ML1 NM_144670.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.328
• 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: Orphanet, ClinGen, Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000282022 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002134025).
• BP6: Variant 12-8874437-A-G is Benign according to our data. Variant chr12-8874437-A-G is described in ClinVar as Benign. ClinVar VariationId is 386368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.4234A>G	p.Thr1412Ala	missense	Exon 34 of 36	NP_653271.3	A8K2U0-1
	A2ML1	NM_001282424.3		c.2761A>G	p.Thr921Ala	missense	Exon 23 of 25	NP_001269353.2	A8K2U0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.4234A>G	p.Thr1412Ala	missense	Exon 34 of 36	ENSP00000299698.7	A8K2U0-1
	A2ML1	ENST00000541459.5	TSL:2	c.2884A>G	p.Thr962Ala	missense	Exon 23 of 25	ENSP00000443174.1	H0YGG5
	A2ML1	ENST00000539547.5	TSL:2	c.2761A>G	p.Thr921Ala	missense	Exon 23 of 25	ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3768 AN: 152110 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00964

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00657 AC: 1639 AN: 249498 AF XY: 0.00500

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00268 AC: 3916 AN: 1461656 Hom.: 155 Cov.: 30 AF XY: 0.00230 AC XY: 1675 AN XY: 727132

African (AFR) AF: 0.0897 AC: 3000 AN: 33452

American (AMR) AF: 0.00593 AC: 265 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111846

Other (OTH) AF: 0.00631 AC: 381 AN: 60384

GnomAD4 genome AF: 0.0250 AC: 3801 AN: 152228 Hom.: 158 Cov.: 32 AF XY: 0.0238 AC XY: 1772 AN XY: 74432

African (AFR) AF: 0.0866 AC: 3596 AN: 41512

American (AMR) AF: 0.00962 AC: 147 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68018

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00880 Hom.: 122

Bravo AF: 0.0293

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0793 AC: 317

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00784 AC: 948

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.33
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.033
Sift	Benign	0.085	T
Sift4G	Benign	0.20	T
Polyphen		0.39	B
Vest4		0.14
MVP		0.030
MPC		0.12
ClinPred		0.0023	T
GERP RS		2.2
Varity_R		0.055
gMVP		0.20
Mutation Taster		=99/1	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: rs7315591; hg19: chr12-9027033;