rs10229820

Positions:

• chr7-117548628-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000003084.11(CFTR):​c.1210-13G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,542,054 control chromosomes in the GnomAD database, including 4,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (610 hom., cov: 30)
  • Exomes 𝑓: 0.078 (3879 hom.)
• Consequence: CFTR ENST00000003084.11 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.455

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-117548628-G-T is Benign according to our data. Variant chr7-117548628-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 162962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117548628-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-13G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6089C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-13G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 13483 AN: 142324 Hom.: 609 Cov.: 30

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0494

Gnomad AMR AF: 0.0800

Gnomad ASJ AF: 0.0831

Gnomad EAS AF: 0.00806

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0838

Gnomad MID AF: 0.128

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0713 AC: 14618 AN: 205052 Hom.: 539 AF XY: 0.0718 AC XY: 8032 AN XY: 111880

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.00522

Gnomad SAS exome AF: 0.0494

Gnomad FIN exome AF: 0.0896

Gnomad NFE exome AF: 0.0856

Gnomad OTH exome AF: 0.0804

GnomAD4 exome AF: 0.0779 AC: 109019 AN: 1399628 Hom.: 3879 Cov.: 39 AF XY: 0.0778 AC XY: 54166 AN XY: 696312

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0414

Gnomad4 ASJ exome AF: 0.0846

Gnomad4 EAS exome AF: 0.00727

Gnomad4 SAS exome AF: 0.0551

Gnomad4 FIN exome AF: 0.0918

Gnomad4 NFE exome AF: 0.0814

Gnomad4 OTH exome AF: 0.0787

GnomAD4 genome AF: 0.0947 AC: 13494 AN: 142426 Hom.: 610 Cov.: 30 AF XY: 0.0935 AC XY: 6491 AN XY: 69442

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0799

Gnomad4 ASJ AF: 0.0831

Gnomad4 EAS AF: 0.00769

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0838

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0380 Hom.: 24

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2014	- -

CFTR-related disorder Benign:3

Benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 29, 2021	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Cystic fibrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2018

Other strong data -

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

Feb 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.031
DANN	Benign	0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10229820; hg19: chr7-117188682;