chr19-18594073-G-C

Variant names:

• chr19-18594073-G-C
• NM_004750.5:c.1247C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004750.5(CRLF1):​c.1247C>G​(p.Thr416Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,061,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: CRLF1 NM_004750.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

Genes affected

CRLF1 (HGNC:2364): (cytokine receptor like factor 1) This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells. Mutations in this gene result in Crisponi syndrome and cold-induced sweating syndrome. [provided by RefSeq, Oct 2009]

CRLF1 Gene-Disease associations (from GenCC):

• Cold-induced sweating syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cold-induced sweating syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21330181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.1247C>G	p.Thr416Arg	missense_variant	Exon 8 of 9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.1247C>G	p.Thr416Arg	missense_variant	Exon 8 of 9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.1252C>G	p.Arg418Gly	missense_variant	Exon 8 of 9			ENSP00000506849.1
CRLF1	ENST00000596360.1	n.62C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRLF1	ENST00000594325.1	n.189+174C>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000377 AC: 4 AN: 1061962 Hom.: 0 Cov.: 42 AF XY: 0.00000574 AC XY: 3 AN XY: 522428

African (AFR) AF: 0.00 AC: 0 AN: 23104

American (AMR) AF: 0.00 AC: 0 AN: 28834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15346

East Asian (EAS) AF: 0.00 AC: 0 AN: 13040

South Asian (SAS) AF: 0.00 AC: 0 AN: 73766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000477 AC: 4 AN: 837978

Other (OTH) AF: 0.00 AC: 0 AN: 38454

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1247C>G (p.T416R) alteration is located in exon 8 (coding exon 8) of the CRLF1 gene. This alteration results from a C to G substitution at nucleotide position 1247, causing the threonine (T) at amino acid position 416 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.60	T
PhyloP100		3.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.026	B
Vest4		0.33
MutPred		0.23		Gain of methylation at T416 (P = 0.0037);
MVP		0.86
MPC		0.44
ClinPred		0.94	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.57
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

hg19: chr19-18704883;