rs1057519743

Variant names:

• chrX-1196852-A-C
• rs1057519743
• NM_022148.4:c.695T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_022148.4(CRLF2):​c.695T>G​(p.Phe232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.523
• Publications: 2 publications found

Genes affected

CRLF2 (HGNC:14281): (cytokine receptor like factor 2) This gene encodes a member of the type I cytokine receptor family. The encoded protein is a receptor for thymic stromal lymphopoietin (TSLP). Together with the interleukin 7 receptor (IL7R), the encoded protein and TSLP activate STAT3, STAT5, and JAK2 pathways, which control processes such as cell proliferation and development of the hematopoietic system. Rearrangement of this gene with immunoglobulin heavy chain gene (IGH) on chromosome 14, or with P2Y purinoceptor 8 gene (P2RY8) on the same X or Y chromosomes is associated with B-progenitor acute lymphoblastic leukemia (ALL) and Down syndrome ALL. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.85264 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF2	NM_022148.4	c.695T>G	p.Phe232Cys	missense_variant	Exon 6 of 8	ENST00000400841.8	NP_071431.2
CRLF2	NM_001012288.3	c.359T>G	p.Phe120Cys	missense_variant	Exon 5 of 7		NP_001012288.2
CRLF2	XM_011546181.3	c.692T>G	p.Phe231Cys	missense_variant	Exon 6 of 8		XP_011544483.1
CRLF2	NR_110830.2	n.889T>G		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF2	ENST00000400841.8	c.695T>G	p.Phe232Cys	missense_variant	Exon 6 of 8	1	NM_022148.4	ENSP00000383641.3
CRLF2	ENST00000381567.8	c.359T>G	p.Phe120Cys	missense_variant	Exon 5 of 7	1		ENSP00000370979.4
CRLF2	ENST00000467626.6	n.*175T>G		non_coding_transcript_exon_variant	Exon 6 of 8	5		ENSP00000485269.1
CRLF2	ENST00000467626.6	n.*175T>G		3_prime_UTR_variant	Exon 6 of 8	5		ENSP00000485269.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lymphoblastic leukemia, acute, with lymphomatous features Pathogenic:1

Oct 02, 2014

Database of Curated Mutations (DoCM)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	17
DEOGEN2	Benign	0.16	T;T;.
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.41	T;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		0.52
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.46		Loss of stability (P = 0.0164);Loss of stability (P = 0.0164);.;
MVP		0.80
MPC		0.43
ClinPred		0.66	D
GERP RS		1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519743; hg19: chrX-1314966; COSMIC: COSV67493408;