7-117536514-AGATTGATTGATT-AGATTGATT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.744-9_744-6delGATT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,535,716 control chromosomes in the GnomAD database, including 38,096 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4348 hom., cov: 25)
  • Exomes 𝑓: 0.21 (33748 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.82
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 7-117536514-AGATT-A is Benign according to our data. Variant chr7-117536514-AGATT-A is described in ClinVar as Benign. ClinVar VariationId is 43579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 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.744-9_744-6delGATT		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.744-33_744-30delGATT		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.744-33_744-30delGATT		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.744-33_744-30delGATT		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35190 AN: 151540 Hom.: 4333 Cov.: 25

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.270 AC: 44068 AN: 163440 AF XY: 0.267

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.415

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.212 AC: 292985 AN: 1384058 Hom.: 33748 AF XY: 0.215 AC XY: 147376 AN XY: 684806

African (AFR) AF: 0.222 AC: 7053 AN: 31784

American (AMR) AF: 0.368 AC: 13330 AN: 36198

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4181 AN: 25160

East Asian (EAS) AF: 0.401 AC: 14704 AN: 36680

South Asian (SAS) AF: 0.338 AC: 27032 AN: 79956

European-Finnish (FIN) AF: 0.296 AC: 13146 AN: 44340

Middle Eastern (MID) AF: 0.182 AC: 1005 AN: 5514

European-Non Finnish (NFE) AF: 0.187 AC: 199745 AN: 1066892

Other (OTH) AF: 0.222 AC: 12789 AN: 57534

GnomAD4 genome AF: 0.232 AC: 35245 AN: 151658 Hom.: 4348 Cov.: 25 AF XY: 0.242 AC XY: 17941 AN XY: 74088

African (AFR) AF: 0.222 AC: 9187 AN: 41410

American (AMR) AF: 0.298 AC: 4524 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3464

East Asian (EAS) AF: 0.416 AC: 2136 AN: 5138

South Asian (SAS) AF: 0.371 AC: 1778 AN: 4794

European-Finnish (FIN) AF: 0.300 AC: 3149 AN: 10498

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13281 AN: 67870

Other (OTH) AF: 0.225 AC: 474 AN: 2110

Alfa AF: 0.125 Hom.: 299

Bravo AF: 0.232

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cystic fibrosis (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=99/1	polymorphism (auto)

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: rs1805171; hg19: chr7-117176568; COSMIC: COSV107197392;