12-8822713-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_144670.6(A2ML1):​c.62C>T​(p.Pro21Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P21A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 1 hom. )

Consequence

A2ML1
NM_144670.6 missense, splice_region

Scores

1
2
16
Splicing: ADA: 0.3091
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.456
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.40965128).
BS2
High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
A2ML1NM_144670.6 linkuse as main transcriptc.62C>T p.Pro21Leu missense_variant, splice_region_variant 1/36 ENST00000299698.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
A2ML1ENST00000299698.12 linkuse as main transcriptc.62C>T p.Pro21Leu missense_variant, splice_region_variant 1/361 NM_144670.6 P1A8K2U0-1
A2ML1-AS1ENST00000537288.1 linkuse as main transcriptn.286+7949G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249534
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135390
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461746
Hom.:
1
Cov.:
30
AF XY:
0.00000963
AC XY:
7
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 16, 2019Variant summary: A2ML1 c.62C>T (p.Pro21Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249534 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.62C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.046
T
Eigen
Benign
-0.023
Eigen_PC
Benign
0.020
FATHMM_MKL
Benign
0.45
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L
MutationTaster
Benign
0.93
D
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Benign
0.24
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.11
T
Polyphen
0.96
D
Vest4
0.25
MutPred
0.76
Loss of glycosylation at P21 (P = 0.0458);
MVP
0.17
MPC
0.11
ClinPred
0.86
D
GERP RS
3.4
Varity_R
0.082
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.31
dbscSNV1_RF
Benign
0.28
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771087097; hg19: chr12-8975309; API