rs121909021

Variant names:

• chr7-117540276-C-T
• rs121909021
• NM_000492.4:c.1046C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM1 PM5 PP2

The NM_000492.4(CFTR):​c.1046C>T​(p.Ala349Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). ClinVar reports functional evidence for this variant: "SCV000603017: Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). PMID:29805046". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A349P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:14
• Conservation: PhyloP100: 7.43
• Publications: 21 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000603017: Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). PMID: 29805046
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 22 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117540275-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 618892.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

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.1046C>T	p.Ala349Val	missense	Exon 8 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1046C>T	p.Ala349Val	missense	Exon 8 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1046C>T	p.Ala349Val	missense	Exon 8 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1046C>T	p.Ala349Val	missense	Exon 8 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 251102 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000308 AC: 450 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 727078

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000374 AC: 416 AN: 1111748

Other (OTH) AF: 0.000497 AC: 30 AN: 60376

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74294

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

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	8	-	Cystic fibrosis (9)
1	4	-	not provided (5)
-	1	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Hereditary pancreatitis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.20	N
PhyloP100		7.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.63
Sift	Benign	0.17	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.49
MVP		1.0
MPC		0.0064
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.81
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909021; hg19: chr7-117180330;