rs373002889

chr7-117627502-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000492.4(CFTR):c.3469-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,612,424 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (21 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 0.263

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-117627502-T-C is Benign according to our data. Variant chr7-117627502-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 7228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000683 (104/152254) while in subpopulation SAS AF= 0.0201 (97/4822). AF 95% confidence interval is 0.0169. There are 3 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3469-20T>C		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3469-20T>C		intron_variant		1	NM_000492.4	P2
	ENST00000456270.1	n.66-11162A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152136 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00148 AC: 371 AN: 249840 Hom.: 7 AF XY: 0.00199 AC XY: 269 AN XY: 135046

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000773 AC: 1129 AN: 1460170 Hom.: 21 Cov.: 31 AF XY: 0.00111 AC XY: 809 AN XY: 726372

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152254 Hom.: 3 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74438

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Benign:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 17, 2000	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous c.3469-20T>C variant in CFTR has been reported in at least 3 individuals with cystic fibrosis without another variant identified in the gene (PMID: 10869121, 20551465, 21520337), and has been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive cystic fibrosis. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 2015	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:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2022	Variant summary: CFTR c.3469-20T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 250478 control chromosomes, predominantly at a frequency of 0.012 within the South Asian subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Cystic Fibrosis (0.012 vs 0.013), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant, c.3469-20T>C, has been reported in the literature in individuals affected with Cystic Fibrosis and idiopathic chronic pancreatitis, without strong evidence for causality (e.g. Kabra_2000, Midha_2010, Steiner_2011, Claustres_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant was also found in a French CF patient as a complex allele in cis with a pathogenic CFTR variant c.3197G>A (p.Arg1066His), suggesting a possibly non-pathogenic role for the variant of interest (Claustres_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The majority classified the variant as either benign (n=3) or likely benign (n=1), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2022	- -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	7.5
Dann	Benign	0.53

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: rs373002889; hg19: chr7-117267556;