rs1800169

Variant names:

• chr11-58624028-G-A
• rs1800169
• NM_000614.4:c.115-6G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BA1

The NM_000614.4(CNTF):​c.115-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,610,680 control chromosomes in the GnomAD database, including 17,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1390 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16024 hom.)
• Consequence: CNTF NM_000614.4 splice_region, intron
• Scores: Splicing: ADA: 0.9940
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.12
• Publications: 41 publications found

Genes affected

CNTF (HGNC:2169): (ciliary neurotrophic factor) The protein encoded by this gene is a polypeptide hormone whose actions appear to be restricted to the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. A read-through transcript variant composed of the upstream ZFP91 gene and CNTF sequence has been identified, but it is thought to be non-coding. Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Oct 2010]

ZFP91-CNTF (HGNC:33441): (ZFP91-CNTF readthrough (NMD candidate)) This gene represents a read-through transcript composed of ZFP91 and CNTF sequence. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Aug 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-58624028-G-A is Benign according to our data. Variant chr11-58624028-G-A is described in ClinVar as Benign. ClinVar VariationId is 17493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTF	NM_000614.4	c.115-6G>A		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000361987.6	NP_000605.1
ZFP91-CNTF	NR_024091.1	n.1845-6G>A		splice_region_variant, intron_variant	Intron 12 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTF	ENST00000361987.6	c.115-6G>A		splice_region_variant, intron_variant	Intron 1 of 1	1	NM_000614.4	ENSP00000355370.4
ZFP91-CNTF	ENST00000389919.8	n.*87-6G>A		splice_region_variant, intron_variant	Intron 12 of 12	2		ENSP00000455911.1
ZFP91-CNTF	ENST00000422974.2	n.*118-6G>A		splice_region_variant, intron_variant	Intron 10 of 10	5		ENSP00000457288.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18923 AN: 151872 Hom.: 1388 Cov.: 32

Gnomad AFR AF: 0.0495

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.149 AC: 36652 AN: 245810 AF XY: 0.154

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.146 AC: 213128 AN: 1458690 Hom.: 16024 Cov.: 32 AF XY: 0.148 AC XY: 107327 AN XY: 725576

African (AFR) AF: 0.0462 AC: 1542 AN: 33390

American (AMR) AF: 0.171 AC: 7566 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3351 AN: 25876

East Asian (EAS) AF: 0.156 AC: 6189 AN: 39688

South Asian (SAS) AF: 0.184 AC: 15750 AN: 85720

European-Finnish (FIN) AF: 0.174 AC: 9271 AN: 53216

Middle Eastern (MID) AF: 0.199 AC: 1140 AN: 5724

European-Non Finnish (NFE) AF: 0.144 AC: 159907 AN: 1110498

Other (OTH) AF: 0.140 AC: 8412 AN: 60246

GnomAD4 genome AF: 0.125 AC: 18927 AN: 151990 Hom.: 1390 Cov.: 32 AF XY: 0.128 AC XY: 9504 AN XY: 74262

African (AFR) AF: 0.0494 AC: 2049 AN: 41494

American (AMR) AF: 0.177 AC: 2697 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.133 AC: 687 AN: 5150

South Asian (SAS) AF: 0.167 AC: 800 AN: 4804

European-Finnish (FIN) AF: 0.172 AC: 1819 AN: 10546

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9975 AN: 67942

Other (OTH) AF: 0.137 AC: 288 AN: 2108

Alfa AF: 0.138 Hom.: 7225

Bravo AF: 0.120

Asia WGS AF: 0.114 AC: 394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CILIARY NEUROTROPHIC FACTOR POLYMORPHISM Benign:1

May 01, 2004

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Benign	0.91
PhyloP100		2.1
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.70		Position offset: 6

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

Other links and lift over

dbSNP: rs1800169; hg19: chr11-58391501; COSMIC: COSV60161810; COSMIC: COSV60161810;