rs34010645

Positions:

• chr7-117504391-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BS1 BS2

The NM_000492.4(CFTR):​c.164+28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,049,952 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (6 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:8
• Conservation: PhyloP100: 0.421

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-117504391-A-G is Benign according to our data. Variant chr7-117504391-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 235283.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=6}. Variant chr7-117504391-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (828/152320) while in subpopulation AFR AF= 0.0186 (773/41582). AF 95% confidence interval is 0.0175. There are 7 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.164+28A>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.164+28A>G		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152202 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00142 AC: 335 AN: 235408 Hom.: 4 AF XY: 0.000943 AC XY: 120 AN XY: 127272

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000805

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000288

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000607 AC: 545 AN: 897632 Hom.: 6 Cov.: 12 AF XY: 0.000487 AC XY: 229 AN XY: 470326

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000270

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000367

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152320 Hom.: 7 Cov.: 32 AF XY: 0.00549 AC XY: 409 AN XY: 74482

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00619

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	CFTR: BS1, BS2 -

Cystic fibrosis Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	- -
Uncertain significance, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2022	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 17, 2017

- -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.9
DANN	Benign	0.86

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: rs34010645; hg19: chr7-117144445;