7-117536514-AGATTGATTGATT-AGATTGATTGATTGATT

Variant names:

• chr7-117536514-A-AGATT
• rs1805171
• NM_000492.4:c.744-9_744-6dupGATT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6_Very_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.744-9_744-6dupGATT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,541,332 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 25)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.444
• 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)

ACMG classification

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

• BP6: Variant 7-117536514-A-AGATT is Benign according to our data. Variant chr7-117536514-A-AGATT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.744-9_744-6dupGATT		splice_region intron	N/A	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.744-34_744-33insGATT		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.744-34_744-33insGATT		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.744-34_744-33insGATT		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 323 AN: 151646 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00161 AC: 263 AN: 163440 AF XY: 0.00145

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000240

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00162 AC: 2255 AN: 1389568 Hom.: 5 Cov.: 23 AF XY: 0.00156 AC XY: 1073 AN XY: 687308

African (AFR) AF: 0.00392 AC: 125 AN: 31896

American (AMR) AF: 0.00320 AC: 116 AN: 36228

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25216

East Asian (EAS) AF: 0.000245 AC: 9 AN: 36754

South Asian (SAS) AF: 0.00112 AC: 90 AN: 80082

European-Finnish (FIN) AF: 0.000405 AC: 18 AN: 44478

Middle Eastern (MID) AF: 0.00253 AC: 14 AN: 5532

European-Non Finnish (NFE) AF: 0.00166 AC: 1784 AN: 1071630

Other (OTH) AF: 0.00170 AC: 98 AN: 57752

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151764 Hom.: 1 Cov.: 25 AF XY: 0.00218 AC XY: 162 AN XY: 74148

African (AFR) AF: 0.00408 AC: 169 AN: 41438

American (AMR) AF: 0.00204 AC: 31 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4800

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10514

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 67892

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000725 Hom.: 299

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Cystic fibrosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1805171; hg19: chr7-117176568; COSMIC: COSV50072820;