rs397508569

Variant names:

• chr7-117614706-A-G
• rs397508569
• NM_000492.4:c.3461A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117614706-A-G
• chr7-117614706-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.3461A>G​(p.Asp1154Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,666 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1154N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 O:1
• Conservation: PhyloP100: 9.14
• Publications: 2 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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 10 ACMG points.

• PM1: In a hotspot region, there are 3 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
• 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, 0.961
• PP5: Variant 7-117614706-A-G is Pathogenic according to our data. Variant chr7-117614706-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53749.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3461A>G	p.Asp1154Gly	missense_variant	Exon 21 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+1523T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3461A>G	p.Asp1154Gly	missense_variant	Exon 21 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250930 AF XY: 0.00000737

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455666 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724528

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106666

Other (OTH) AF: 0.0000166 AC: 1 AN: 60162

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:1 Other:1

Jul 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1154G variant (also known as c.3461A>G), located in coding exon 21 of the CFTR gene, results from an A to G substitution at nucleotide position 3461. The aspartic acid at codon 1154 is replaced by glycine, an amino acid with similar properties. In one functional study, this alteration impacted the proper gating of the chloride channel (Vankeerberghen A et al. FEBS Lett, 1998 Oct;437:1-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

CFTR-related disorder Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Uncertain:1

May 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3461A>G (p.Asp1154Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250930 control chromosomes. c.3461A>G has been reported in the literature as a non-informative genotype (second allele not specified) in individuals affected with CBAVD/CAVD and Cystic Fibrosis (Claustres_2000, Green_2010, Yang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis/CFTR-related disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel activity (Vankeerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 20932301, 9804160, 26277102). CFTR-France database has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

May 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in at least one individual with congenital absence of the vas deferens who also harbored a second CFTR variant, but segregation data and additional clinical information was not included (Claustres et al., 2000; Costes et al., 1995; De Braekeleer et al., 1996); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28603918, 20059485, 9804160, 31674704, 8556303, 9239681, 16442101, 12940920, 10923036) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.
PhyloP100		9.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.90
MutPred		0.84		Gain of MoRF binding (P = 0.0325);.;.;.;.;
MVP		0.99
MPC		0.0052
ClinPred		0.99	D
GERP RS		5.9
PromoterAI		-0.026	Neutral
Varity_R		0.97
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs397508569; hg19: chr7-117254760;