rs17792974

Variant names:

• chr12-8823305-C-T
• rs17792974
• NM_144670.6:c.186C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_144670.6(A2ML1):​c.186C>T​(p.Thr62Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 1,613,902 control chromosomes in the GnomAD database, including 5,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (418 hom., cov: 32)
  • Exomes 𝑓: 0.061 (4807 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.259
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-8823305-C-T is Benign according to our data. Variant chr12-8823305-C-T is described in ClinVar as Benign. ClinVar VariationId is 384687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.244 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.186C>T	p.Thr62Thr	synonymous	Exon 2 of 36	NP_653271.3
	A2ML1-AS1	NR_046715.1		n.645+7357G>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.186C>T	p.Thr62Thr	synonymous	Exon 2 of 36	ENSP00000299698.7
	A2ML1-AS1	ENST00000537288.1	TSL:3	n.286+7357G>A		intron	N/A
	A2ML1	ENST00000537546.1	TSL:4	n.-208C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0569 AC: 8649 AN: 151974 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.0546

GnomAD2 exomes AF: 0.0879 AC: 21924 AN: 249524 AF XY: 0.0942

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0460

Gnomad OTH exome AF: 0.0747

GnomAD4 exome AF: 0.0609 AC: 88978 AN: 1461810 Hom.: 4807 Cov.: 31 AF XY: 0.0659 AC XY: 47920 AN XY: 727214

African (AFR) AF: 0.0350 AC: 1173 AN: 33476

American (AMR) AF: 0.0747 AC: 3341 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 1773 AN: 26132

East Asian (EAS) AF: 0.189 AC: 7490 AN: 39694

South Asian (SAS) AF: 0.234 AC: 20218 AN: 86236

European-Finnish (FIN) AF: 0.0622 AC: 3322 AN: 53418

Middle Eastern (MID) AF: 0.0794 AC: 458 AN: 5768

European-Non Finnish (NFE) AF: 0.0423 AC: 46983 AN: 1111968

Other (OTH) AF: 0.0699 AC: 4220 AN: 60396

GnomAD4 genome AF: 0.0569 AC: 8658 AN: 152092 Hom.: 418 Cov.: 32 AF XY: 0.0628 AC XY: 4668 AN XY: 74350

African (AFR) AF: 0.0358 AC: 1483 AN: 41468

American (AMR) AF: 0.0579 AC: 884 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1038 AN: 5168

South Asian (SAS) AF: 0.256 AC: 1232 AN: 4816

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0439 AC: 2982 AN: 67996

Other (OTH) AF: 0.0573 AC: 121 AN: 2110

Alfa AF: 0.0463 Hom.: 255

Bravo AF: 0.0538

Asia WGS AF: 0.187 AC: 651 AN: 3478

EpiCase AF: 0.0482

EpiControl AF: 0.0468

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.1
DANN	Benign	0.86
PhyloP100		-0.26
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: rs17792974; hg19: chr12-8975901; COSMIC: COSV55292760; COSMIC: COSV55292760;