Genetic Variant CRLF1:p.Arg364Arg (chr19-18594367-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004750.5(CRLF1):c.1092G>A(p.Arg364Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,608,466 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

CRLF1
NM_004750.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.750

Publications

1 publications found

Variant links:

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

CRLF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 19-18594367-C-T is Benign according to our data. Variant chr19-18594367-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2155811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.75 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00045 (68/151234) while in subpopulation AMR AF = 0.00164 (25/15238). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004750.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF1	NM_004750.5	MANE Select	c.1092G>A	p.Arg364Arg	synonymous	Exon 7 of 9	NP_004741.1	O75462

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRLF1	ENST00000392386.8	TSL:1 MANE Select	c.1092G>A	p.Arg364Arg	synonymous	Exon 7 of 9	ENSP00000376188.2	O75462
CRLF1	ENST00000928241.1		c.1173G>A	p.Arg391Arg	synonymous	Exon 8 of 10	ENSP00000598300.1
CRLF1	ENST00000971859.1		c.1158G>A	p.Arg386Arg	synonymous	Exon 8 of 10	ENSP00000641918.1

Frequencies

GnomAD3 genomes

AF:

0.000437

AC:

AN:

151126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000325

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000616

AC:

147

AN:

238794

AF XY:

0.000764

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.000619

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000569

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.000366

AC:

533

AN:

1457232

Hom.:

Cov.:

AF XY:

0.000428

AC XY:

310

AN XY:

724410

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33386

American (AMR)

AF:

0.000675

AC:

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39562

South Asian (SAS)

AF:

0.00112

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51936

Middle Eastern (MID)

AF:

0.00401

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000239

AC:

265

AN:

1110034

Other (OTH)

AF:

0.000964

AC:

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000450

AC:

AN:

151234

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

73906

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41240

American (AMR)

AF:

0.00164

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5034

South Asian (SAS)

AF:

0.00146

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000325

AC:

AN:

67684

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000676

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over