12-8823315-C-T

Variant names:

• chr12-8823315-C-T
• rs185519272
• NM_144670.6:c.196C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_144670.6(A2ML1):​c.196C>T​(p.Leu66Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,614,144 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (22 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.373
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-8823315-C-T is Benign according to our data. Variant chr12-8823315-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.373 with no splicing effect.
• BS2: High AC in GnomAd4 at 283 AD gene.

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.196C>T	p.Leu66Leu	synonymous	Exon 2 of 36	NP_653271.3
	A2ML1-AS1	NR_046715.1		n.645+7347G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.196C>T	p.Leu66Leu	synonymous	Exon 2 of 36	ENSP00000299698.7
	A2ML1-AS1	ENST00000537288.1	TSL:3	n.286+7347G>A		intron	N/A
	A2ML1	ENST00000537546.1	TSL:4	n.-198C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00270 AC: 673 AN: 249518 AF XY: 0.00302

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00330 AC: 4825 AN: 1461872 Hom.: 22 Cov.: 31 AF XY: 0.00343 AC XY: 2498 AN XY: 727240

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00568 AC: 490 AN: 86258

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53416

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00347 AC: 3859 AN: 1111996

Other (OTH) AF: 0.00389 AC: 235 AN: 60396

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74458

African (AFR) AF: 0.000529 AC: 22 AN: 41550

American (AMR) AF: 0.000851 AC: 13 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

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

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00181

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00403

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Otitis media, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.6
DANN	Benign	0.88
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs185519272; hg19: chr12-8975911;