15-44711547-A-T

Variant names:

• chr15-44711547-A-T
• rs1023835002
• NM_004048.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_004048.4(B2M):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: B2M NM_004048.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 13 publications found

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)

ACMG classification

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	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B2M	NM_004048.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	NP_004039.1
	PATL2	NM_001387263.1	MANE Select	c.-781T>A		upstream_gene	N/A	NP_001374192.1
	PATL2	NM_001387261.1		c.-603T>A		upstream_gene	N/A	NP_001374190.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B2M	ENST00000648006.3	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000497910.1
	B2M	ENST00000559916.1	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 3	ENSP00000453350.1
	B2M	ENST00000557901.5	TSL:1	n.1A>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000452861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.68	T
PhyloP100		2.1
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.83	P
Vest4		0.83
MutPred		0.86		Loss of catalytic residue at M1 (P = 0.0348)
MVP		0.94
ClinPred		0.84	D
GERP RS		5.3
PromoterAI		-0.024	Neutral
Varity_R		0.98
gMVP		0.47
Mutation Taster		=32/168	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

Other links and lift over

dbSNP: rs1023835002; hg19: chr15-45003745; COSMIC: COSV62562840; COSMIC: COSV62562840;