NM_000492.4:c.3717+5885dupT

Variant names:

• chr7-117633643-G-GT
• rs965265631
• NM_000492.4:c.3717+5885dupT

Variant summary

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

The NM_000492.4(CFTR):​c.3717+5885dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000821 in 144,964 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00082 (1 hom., cov: 32)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.955
• 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 0 ACMG points.

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.3717+5885dupT		intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.65+13707dupA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3717+5873_3717+5874insT		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3711+5873_3711+5874insT		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3630+5873_3630+5874insT		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 119 AN: 144918 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000432

Gnomad FIN AF: 0.00457

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.000658

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000821 AC: 119 AN: 144964 Hom.: 1 Cov.: 32 AF XY: 0.000838 AC XY: 59 AN XY: 70438

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000300 AC: 12 AN: 39952

American (AMR) AF: 0.00124 AC: 18 AN: 14536

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3360

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5002

South Asian (SAS) AF: 0.000434 AC: 2 AN: 4612

European-Finnish (FIN) AF: 0.00457 AC: 41 AN: 8962

Middle Eastern (MID) AF: 0.00362 AC: 1 AN: 276

European-Non Finnish (NFE) AF: 0.000658 AC: 43 AN: 65378

Other (OTH) AF: 0.00 AC: 0 AN: 1986

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95

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

Other links and lift over

dbSNP: rs965265631; hg19: chr7-117273697;