NM_000492.4:c.1407G>A

Variant names:

• chr7-117559478-G-A
• rs143218779
• NM_000492.4:c.1407G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000492.4(CFTR):​c.1407G>A​(p.Met469Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M469V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.43
• Publications: 8 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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117559476-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1407G>A	p.Met469Ile	missense_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1255C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1407G>A	p.Met469Ile	missense_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251252 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452206 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723208

African (AFR) AF: 0.00 AC: 0 AN: 33054

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103680

Other (OTH) AF: 0.00 AC: 0 AN: 60024

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1407G>A; p.Met469Ile variant (rs143218779) is reported in the literature in several individuals affected with congenital bilateral absence of the vas deferens (CBAVD) (Chiang 2019, Wu 2005). This variant found on only a single chromosome in the Genome Aggregation Database (1/251252 alleles), indicating it is not a common polymorphism. The methionine at codon 469 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, another amino acid substitution at this codon (p.Met469Val) has been reported in individuals with CBAVD or pancreatitis (Lu 2013, Lu 2014, Xiao 2017). Nonetheless, due to limited information, the clinical significance of the p.Met469Ile variant is uncertain at this time. References: Chiang HS et al. The role of SLC9A3 in Taiwanese patients with congenital bilateral absence of vas deferens (CBAVD). J Formos Med Assoc. 2019 Feb 20. pii: S0929-6646(18)30529-1. Lu S et al. Association of cystic fibrosis transmembrane-conductance regulator gene mutation with negative outcome of intracytoplasmic sperm injection pregnancy in cases of congenital bilateral absence of vas deferens. Fertil Steril. 2014 May;101(5):1255-60. Lu S et al. Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia. Urology. 2013 Oct;82(4):824-8. Wu CC et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005 Sep;20(9):2470-5. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. -

CFTR-related disorder Uncertain:1

Jul 07, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.7	L;.;.;.;.
PhyloP100		9.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;.;.;N;.
REVEL	Pathogenic	0.82
Sift	Benign	0.069	T;.;.;T;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.82
MutPred		0.91		Gain of methylation at K464 (P = 0.0863);.;.;.;.;
MVP		1.0
MPC		0.0040
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.93
Mutation Taster		=7/93	disease causing

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: rs143218779; hg19: chr7-117199532;