7-117548606-ATGTGTGTG-ATGTGTGTGTG

Position:

• chr7-117548606-ATGTGTGTG-ATGTGTGTGTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1210-13_1210-12dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.13 (1779 hom., cov: 0)
  • Exomes 𝑓: 0.12 (2389 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0650

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-117548606-A-ATG is Benign according to our data. Variant chr7-117548606-A-ATG is described in ClinVar as [Benign]. Clinvar id is 229652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-13_1210-12dupGT		intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6069_222-6068dupCA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-13_1210-12dupGT		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.130 AC: 18711 AN: 143394 Hom.: 1778 Cov.: 0

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0725

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.199 AC: 35369 AN: 177682 Hom.: 631 AF XY: 0.195 AC XY: 18633 AN XY: 95626

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.429

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.121 AC: 164900 AN: 1367614 Hom.: 2389 Cov.: 0 AF XY: 0.123 AC XY: 83442 AN XY: 679818

Gnomad4 AFR exome AF: 0.0762

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.0889

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0985

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.131 AC: 18730 AN: 143494 Hom.: 1779 Cov.: 0 AF XY: 0.137 AC XY: 9537 AN XY: 69734

Gnomad4 AFR AF: 0.0788

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.0911

Gnomad4 EAS AF: 0.502

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.127

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2021	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2018

The c.1210-34TG[12]T[7] allele in intron 9 of the CFTR gene is classified as be nign because it has been identified in 43% (6544/15040) of East Asian chromosome s in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs3832534). 930 homozygotes have also been identfied in the gnomAD databas e. ACMG/AMP Criteria applied: BA1 -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.64
BranchPoint Hunter		2.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3832534; hg19: chr7-117188660;