rs397508189

Variant names:

• chr7-117548756-A-AAGAT
• rs397508189
• NM_000492.4:c.1327_1330dupGATA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1327_1330dupGATA​(p.Ile444ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I444I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 1.88
• Publications: 8 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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117548756-A-AAGAT is Pathogenic according to our data. Variant chr7-117548756-A-AAGAT is described in ClinVar as Pathogenic. ClinVar VariationId is 188958.Status of the report is reviewed_by_expert_panel, 3 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.1327_1330dupGATA	p.Ile444ArgfsTer3	frameshift	Exon 10 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6221_222-6218dupATCT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1327_1330dupGATA	p.Ile444ArgfsTer3	frameshift	Exon 10 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1327_1330dupGATA	p.Ile444ArgfsTer3	frameshift	Exon 10 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.1327_1330dupGATA	p.Ile444ArgfsTer3	frameshift	Exon 10 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000248 AC: 6 AN: 242172 AF XY: 0.0000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000462

Gnomad OTH exome AF: 0.000169

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000171 AC: 25 AN: 1460694 Hom.: 0 Cov.: 36 AF XY: 0.0000179 AC XY: 13 AN XY: 726626

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111370

Other (OTH) AF: 0.0000166 AC: 1 AN: 60296

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Cystic fibrosis (8)
3	-	-	CFTR-related disorder (3)
3	-	-	not provided (3)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397508189; hg19: chr7-117188810;