chr15-44711581-T-C

Position:

• chr15-44711581-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004048.4(B2M):​c.35T>C​(p.Leu12Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: B2M NM_004048.4 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 3.80

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B2M	NM_004048.4	c.35T>C	p.Leu12Pro	missense_variant	1/4	ENST00000648006.3
B2M	XM_005254549.4	c.35T>C	p.Leu12Pro	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B2M	ENST00000648006.3	c.35T>C	p.Leu12Pro	missense_variant	1/4		NM_004048.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;D;D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;M;M;M
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;.
Polyphen		1.0	D;D;D;D
Vest4		0.84
MutPred		0.78		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.88
MPC		1.7
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45003779; COSMIC: COSV62563197; COSMIC: COSV62563197;