7-117611743-T-G

Position:

• chr7-117611743-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000003084.11(CFTR):​c.3302T>G​(p.Met1101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1101K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR ENST00000003084.11 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.93

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000003084.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611743-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 39516.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-117611743-T-G is Pathogenic according to our data. Variant chr7-117611743-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 53712.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611743-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3302T>G	p.Met1101Arg	missense_variant	20/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3302T>G	p.Met1101Arg	missense_variant	20/27	1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.177+4486A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 21, 2019	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Met1101 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7680525, 17901983, 22981120). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect CFTR protein function (PMID:8662892) This variant has been observed in a family with cystic fibrosis (PMID: 28544683). It has also been observed in affected individuals, however no second CFTR variant was reported (PMID:7683628, 23276700). ClinVar contains an entry for this variant (Variation ID: 53712). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 1101 of the CFTR protein (p.Met1101Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 11, 2019	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2016

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.;D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.99
MutPred		0.96		Gain of MoRF binding (P = 0.0124);.;.;.;.;
MVP		1.0
MPC		0.0073
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.97

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: rs36210737; hg19: chr7-117251797;