7-117548628-GTTTTTT-GTTTT

Variant names:

• chr7-117548628-GTT-G
• rs1805177
• NM_000492.4:c.1210-7_1210-6delTT

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP5 BA1

The NM_000492.4(CFTR):​c.1210-7_1210-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,547,804 control chromosomes in the GnomAD database, including 354 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.036 (122 hom., cov: 31)
  • Exomes 𝑓: 0.029 (232 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:3 O:4
• Conservation: PhyloP100: 0.565
• Publications: 6 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: Benign. The variant received -7 ACMG points.

• PP5: Variant 7-117548628-GTT-G is Pathogenic according to our data. Variant chr7-117548628-GTT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242535.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

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.1210-7_1210-6delTT		splice_region intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6091_222-6090delAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1210-12_1210-11delTT		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1210-12_1210-11delTT		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1210-12_1210-11delTT		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5089 AN: 142494 Hom.: 122 Cov.: 31

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.0449

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00812

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0303

GnomAD2 exomes AF: 0.0223 AC: 4575 AN: 205052 AF XY: 0.0219

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0286 AC: 40213 AN: 1405206 Hom.: 232 AF XY: 0.0278 AC XY: 19403 AN XY: 699172

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

African (AFR) AF: 0.0558 AC: 1730 AN: 30984

American (AMR) AF: 0.0101 AC: 432 AN: 42846

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 438 AN: 24246

East Asian (EAS) AF: 0.000419 AC: 16 AN: 38208

South Asian (SAS) AF: 0.00648 AC: 541 AN: 83510

European-Finnish (FIN) AF: 0.0276 AC: 1430 AN: 51808

Middle Eastern (MID) AF: 0.0110 AC: 61 AN: 5532

European-Non Finnish (NFE) AF: 0.0316 AC: 33837 AN: 1070510

Other (OTH) AF: 0.0300 AC: 1728 AN: 57562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0357 AC: 5090 AN: 142598 Hom.: 122 Cov.: 31 AF XY: 0.0351 AC XY: 2439 AN XY: 69528

African (AFR) AF: 0.0620 AC: 2294 AN: 36978

American (AMR) AF: 0.0167 AC: 241 AN: 14402

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 64 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00857 AC: 39 AN: 4552

European-Finnish (FIN) AF: 0.0328 AC: 317 AN: 9670

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.0311 AC: 2033 AN: 65382

Other (OTH) AF: 0.0300 AC: 59 AN: 1966

Alfa AF: 0.00983 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	2	-	Cystic fibrosis (8)
6	-	-	not provided (6)
3	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (3)
1	1	-	not specified (2)
1	-	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	Hereditary pancreatitis (1)
1	-	-	Obstructive azoospermia (1)
-	-	-	Bronchiectasis with or without elevated sweat chloride 1, modifier of (1)
-	-	-	Congenital bilateral absence of vas deferens (1)
-	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1805177; hg19: chr7-117188682;