rs76151804

Variant names:

• chr7-117611555-A-G
• rs76151804
• NM_000492.4:c.3140-26A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117611555-A-G
• chr7-117611555-A-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.3140-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,312,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000052170: The most pronounced variant effect results in <10% of normal activity (Beck_1999)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: -0.133
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052170: The most pronounced variant effect results in <10% of normal activity (Beck_1999).; SCV000074807: Studies have shown that this variant alters CFTR gene expression (PMID: 12397022, 23974870).; SCV002107084: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 10425036) - PS3_supporting."; SCV001549256: Multiple functional studies have confirmed this aberrant splicing and have determined that this variant extends exon 20 by 25 base pairs, which causes a frameshift leading to a premature stop codon (Sanz_2017_PMID: 28863137; Beck_1999_PMID:10425036; Ramalho_2002_PMID: 12397022).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117611555-A-G is Pathogenic according to our data. Variant chr7-117611555-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 35864.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.3140-26A>G		intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4674T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3140-26A>G		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3140-26A>G		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3053-26A>G		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000423 AC: 10 AN: 236632 AF XY: 0.0000550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000904

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000668

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000108 AC: 125 AN: 1160806 Hom.: 0 Cov.: 16 AF XY: 0.000105 AC XY: 62 AN XY: 591218

African (AFR) AF: 0.0000721 AC: 2 AN: 27756

American (AMR) AF: 0.0000695 AC: 3 AN: 43174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24114

East Asian (EAS) AF: 0.00 AC: 0 AN: 38192

South Asian (SAS) AF: 0.0000506 AC: 4 AN: 78974

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5180

European-Non Finnish (NFE) AF: 0.000132 AC: 111 AN: 839970

Other (OTH) AF: 0.0000791 AC: 4 AN: 50544

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
12	-	-	Cystic fibrosis (12)
8	-	-	not provided (8)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Uncertain	25
DANN	Benign	0.77
PhyloP100		-0.13
PromoterAI		0.012	Neutral
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 1
DS_AL_spliceai		0.42		Position offset: 26

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

Other links and lift over

dbSNP: rs76151804; hg19: chr7-117251609; COSMIC: COSV50081323; COSMIC: COSV50081323;