rs1554392248

Positions:

• chr7-117611721-TCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TTGTTAA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Moderate PM2 PP3 PP5_Moderate

The NM_000492.4(CFTR):​c.3281_3367+268delinsTGTTAA variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1094S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR NM_000492.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.89

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.051091604 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-117611722-CAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TGTTAA is Pathogenic according to our data. Variant chr7-117611722-CAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TGTTAA is described in ClinVar as [Pathogenic]. Clinvar id is 53703.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3281_3367+268delinsTGTTAA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3281_3367+268delinsTGTTAA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	20/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+4153_177+4507delinsTTAACA		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2019	Variant summary: This CFTR c.3281_3367+268delinsTGTTAA variant leads to a partial deletion of exon 20 as well as the overlapping the splice-donor site. This would either lead to a deletion of 28 amino acids from exon 20 and subsequently would be predicted to impact protein function or disrupt normal splicing. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. c.3281_3367+268delinsTGTTAA has been reported in the literature in individuals affected with Cystic Fibrosis (Niel_2004; Ferec_2006) as we reputed databases (sick kids) that cited this variant as having been identified on the maternal chromosome of a 10 year old boy who was diagnosed with CF at 1 year because of failure to thrive. He was reported as pancreatically insufficient, lung colonization with Pseudomonas aeruginosa. His sweat test was reportedly clearly positive. He carried p.F508del on the other chromosome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Furthermore, another deletion variant which involves complete deletion of exon 20 has also been reported in a CF patient (PMID: 8682493). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554392248; hg19: chr7-117251776;