rs1554395323

Variant names:

• chr7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A
• rs1554395323
• NM_000492.4:c.3718-24_3873+601del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_000492.4(CFTR):​c.3718-24_3873+601del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035111412 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A is Pathogenic according to our data. Variant chr7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 53792.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. 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
	CFTR	NM_000492.4	MANE Select	c.3718-24_3873+601del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 23 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.65+4160_65+4940del		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3718-27_3873+598del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 23 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3712-27_3867+598del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 23 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3631-27_3786+598del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 22 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cystic fibrosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7

Splicing

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

Other links and lift over

dbSNP: rs1554395323; hg19: chr7-117282464;