22-36922208-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000395.3(CSF2RB):c.1A>T(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSF2RB NM_000395.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

Genes affected

CSF2RB (HGNC:2436): (colony stimulating factor 2 receptor subunit beta) The protein encoded by this gene is the common beta chain of the high affinity receptor for IL-3, IL-5 and CSF. Defects in this gene have been reported to be associated with protein alveolar proteinosis (PAP). [provided by RefSeq, Jul 2008]

LOC105373023 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RB	NM_000395.3	c.1A>T	p.Met1?	start_lost	2/14	ENST00000403662.8
LOC105373023	XR_938230.2	n.195-3269T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RB	ENST00000403662.8	c.1A>T	p.Met1?	start_lost	2/14	5	NM_000395.3	P1
CSF2RB	ENST00000406230.5	c.1A>T	p.Met1?	start_lost	1/13	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with CSF2RB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CSF2RB mRNA. The next in-frame methionine is located at codon 10. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	19
Dann	Benign	0.84
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.96	D;.;D
Vest4		0.83
MutPred		0.71		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.91
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.86
gMVP		0.57

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: chr22-37318250;