rs7297690

Variant names:

• chr12-8823009-A-G
• rs7297690
• NM_144670.6:c.63-173A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144670.6(A2ML1):​c.63-173A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,002 control chromosomes in the GnomAD database, including 6,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6201 hom., cov: 32)
• Consequence: A2ML1 NM_144670.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890
• Publications: 4 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-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-8823009-A-G is Benign according to our data. Variant chr12-8823009-A-G is described in ClinVar as Benign. ClinVar VariationId is 561550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 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.63-173A>G		intron	N/A	NP_653271.3	A8K2U0-1
	A2ML1-AS1	NR_046715.1		n.645+7653T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.63-173A>G		intron	N/A	ENSP00000299698.7	A8K2U0-1
	A2ML1-AS1	ENST00000537288.1	TSL:3	n.286+7653T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41809 AN: 151884 Hom.: 6196 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.214

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.275 AC: 41830 AN: 152002 Hom.: 6201 Cov.: 32 AF XY: 0.283 AC XY: 20981 AN XY: 74266

African (AFR) AF: 0.219 AC: 9080 AN: 41462

American (AMR) AF: 0.264 AC: 4026 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2337 AN: 5158

South Asian (SAS) AF: 0.512 AC: 2469 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3884 AN: 10554

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18529 AN: 67958

Other (OTH) AF: 0.218 AC: 459 AN: 2108

Alfa AF: 0.268 Hom.: 8448

Bravo AF: 0.261

Asia WGS AF: 0.433 AC: 1504 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.2
DANN	Benign	0.39
PhyloP100		0.089
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	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: rs7297690; hg19: chr12-8975605; COSMIC: COSV55289772; COSMIC: COSV55289772;