rs398122820

Positions:

• chr15-44715641-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004048.4(B2M):​c.286G>A​(p.Asp96Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: B2M NM_004048.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-44715641-G-A is Pathogenic according to our data. Variant chr15-44715641-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31907.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-44715641-G-A is described in UniProt as null. Variant chr15-44715641-G-A is described in UniProt as null. Variant chr15-44715641-G-A is described in UniProt as null. Variant chr15-44715641-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3139421). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B2M	NM_004048.4	c.286G>A	p.Asp96Asn	missense_variant	2/4	ENST00000648006.3	NP_004039.1
B2M	XM_005254549.4	c.286G>A	p.Asp96Asn	missense_variant	2/2		XP_005254606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B2M	ENST00000648006.3	c.286G>A	p.Asp96Asn	missense_variant	2/4		NM_004048.4	ENSP00000497910	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Non-Hodgkin lymphoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Familial visceral amyloidosis, Ostertag type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 14, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T;T;T;T
Eigen	Benign	0.060
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	.;M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	.;D;D;.
REVEL	Benign	0.22
Sift	Uncertain	0.015	.;D;D;.
Sift4G	Uncertain	0.039	D;D;D;.
Polyphen		0.070	.;B;B;B
Vest4		0.31
MutPred		0.55		.;Loss of phosphorylation at Y98 (P = 0.0691);Loss of phosphorylation at Y98 (P = 0.0691);Loss of phosphorylation at Y98 (P = 0.0691);
MVP		0.75
MPC		1.2
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs398122820; hg19: chr15-45007839;