rs1800502

Positions:

• chr7-117535451-A-G

Variant summary

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

The NM_000492.4(CFTR):​c.743+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,595,360 control chromosomes in the GnomAD database, including 2,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (148 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1972 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.207

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-117535451-A-G is Benign according to our data. Variant chr7-117535451-A-G is described in ClinVar as [Benign]. Clinvar id is 256256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.743+40A>G		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.743+40A>G		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5551 AN: 151504 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.0751

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0600

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0375

GnomAD3 exomes AF: 0.0392 AC: 9759 AN: 248686 Hom.: 219 AF XY: 0.0415 AC XY: 5590 AN XY: 134652

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.0395

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0524

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0499 AC: 71992 AN: 1443742 Hom.: 1972 Cov.: 28 AF XY: 0.0499 AC XY: 35874 AN XY: 719270

Gnomad4 AFR exome AF: 0.00781

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0431

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0543

Gnomad4 OTH exome AF: 0.0510

GnomAD4 genome AF: 0.0366 AC: 5554 AN: 151618 Hom.: 148 Cov.: 32 AF XY: 0.0364 AC XY: 2693 AN XY: 74060

Gnomad4 AFR AF: 0.00896

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0459

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0380

Gnomad4 FIN AF: 0.0600

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0371

Alfa AF: 0.0451 Hom.: 42

Bravo AF: 0.0330

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:3

Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 27, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.97
DANN	Benign	0.32

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: rs1800502; hg19: chr7-117175505;