chr12-8851844-G-A

Position:

• chr12-8851844-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144670.6(A2ML1):​c.2295G>A​(p.Ala765=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,166 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (14 hom.)
• Consequence: A2ML1 NM_144670.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.76

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-8851844-G-A is Benign according to our data. Variant chr12-8851844-G-A is described in ClinVar as [Benign]. Clinvar id is 241891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8851844-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00884 (1346/152278) while in subpopulation AFR AF= 0.0299 (1244/41546). AF 95% confidence interval is 0.0286. There are 20 homozygotes in gnomad4. There are 634 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1346 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6	c.2295G>A	p.Ala765=	synonymous_variant	19/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12	c.2295G>A	p.Ala765=	synonymous_variant	19/36	1	NM_144670.6	ENSP00000299698	P1
A2ML1	ENST00000541459.5	c.945G>A	p.Ala315=	synonymous_variant	8/25	2		ENSP00000443174
A2ML1	ENST00000539547.5	c.822G>A	p.Ala274=	synonymous_variant	8/25	2		ENSP00000438292

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1336 AN: 152160 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00220 AC: 548 AN: 249554 Hom.: 4 AF XY: 0.00173 AC XY: 234 AN XY: 135396

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000833 AC: 1218 AN: 1461888 Hom.: 14 Cov.: 30 AF XY: 0.000708 AC XY: 515 AN XY: 727244

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152278 Hom.: 20 Cov.: 32 AF XY: 0.00851 AC XY: 634 AN XY: 74462

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00322 Hom.: 2

Bravo AF: 0.0101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79067860; hg19: chr12-9004440; COSMIC: COSV105889051; COSMIC: COSV105889051;