15-44711577-G-T

Position:

• chr15-44711577-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5 BP4_Moderate

The NM_004048.4(B2M):​c.31G>T​(p.Ala11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: B2M NM_004048.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.286

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]

B2M (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-44711577-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10131407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B2M	NM_004048.4	c.31G>T	p.Ala11Ser	missense_variant	1/4	ENST00000648006.3	NP_004039.1
B2M	XM_005254549.4	c.31G>T	p.Ala11Ser	missense_variant	1/2		XP_005254606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B2M	ENST00000648006.3	c.31G>T	p.Ala11Ser	missense_variant	1/4		NM_004048.4	ENSP00000497910.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727126

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.81
DEOGEN2	Benign	0.032	T;T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	.;L;L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.95	N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.41	T;T;T;.
Sift4G	Benign	0.39	T;T;T;.
Polyphen		0.49	P;B;B;B
Vest4		0.25
MutPred		0.53		Gain of disorder (P = 0.051);Gain of disorder (P = 0.051);Gain of disorder (P = 0.051);Gain of disorder (P = 0.051);
MVP		0.33
MPC		0.69
ClinPred		0.45	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.53

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: rs104894481; hg19: chr15-45003775;