GeneBe

rs1057519877

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_004048.4(B2M):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

B2M
NM_004048.4 start_lost

Scores

4
6
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.76

Publications

11 publications found
Variant links:
Genes affected
B2M (HGNC:914): (beta-2-microglobulin) This gene encodes a serum protein found in association with the major histocompatibility complex (MHC) class I heavy chain on the surface of nearly all nucleated cells. The protein has a predominantly beta-pleated sheet structure that can form amyloid fibrils in some pathological conditions. The encoded antimicrobial protein displays antibacterial activity in amniotic fluid. A mutation in this gene has been shown to result in hypercatabolic hypoproteinemia.[provided by RefSeq, Aug 2014]
PATL2 (HGNC:33630): (PAT1 homolog 2) Predicted to enable RNA binding activity. Predicted to be involved in P-body assembly and deadenylation-dependent decapping of nuclear-transcribed mRNA. Predicted to act upstream of or within negative regulation of cytoplasmic mRNA processing body assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
PATL2 Gene-Disease associations (from GenCC):
  • oocyte maturation defect 4
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 119 codons. Genomic position: 44716337. Lost 0.986 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
B2M
NM_004048.4
MANE Select
c.3G>Ap.Met1?
start_lost
Exon 1 of 4NP_004039.1
PATL2
NM_001387263.1
MANE Select
c.-783C>T
upstream_gene
N/ANP_001374192.1
PATL2
NM_001387261.1
c.-605C>T
upstream_gene
N/ANP_001374190.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
B2M
ENST00000648006.3
MANE Select
c.3G>Ap.Met1?
start_lost
Exon 1 of 4ENSP00000497910.1
B2M
ENST00000559916.1
TSL:1
c.3G>Ap.Met1?
start_lost
Exon 1 of 3ENSP00000453350.1
B2M
ENST00000557901.5
TSL:1
n.3G>A
non_coding_transcript_exon
Exon 1 of 4ENSP00000452861.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461534
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727090
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53072
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60388
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Benign
-0.93
T
PhyloP100
4.8
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.28
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.93
P
Vest4
0.84
MutPred
0.87
Loss of methylation at R3 (P = 0.0966)
MVP
0.90
ClinPred
0.98
D
GERP RS
5.3
PromoterAI
-0.042
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.96
gMVP
0.56
Mutation Taster
=28/172
disease causing (ClinVar)

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

Publications

Other links and lift over

dbSNP: rs1057519877; hg19: chr15-45003747; COSMIC: COSV62562849; COSMIC: COSV62562849; API