chr7-117603720-A-T

Position:

• chr7-117603720-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.2846A>T​(p.His949Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,950 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).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 O:1
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 50) in uniprot entity CFTR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-117603720-A-T is Pathogenic according to our data. Variant chr7-117603720-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53578.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2846A>T	p.His949Leu	missense_variant	17/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2846A>T	p.His949Leu	missense_variant	17/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251382 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2022	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 949 of the CFTR protein (p.His949Leu). This variant is present in population databases (rs397508444, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 16189704, 21931512). ClinVar contains an entry for this variant (Variation ID: 53578). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	Variant summary: CFTR c.2846A>T (p.His949Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2846A>T has been reported in the literature in at least one individual with atypical CF and equivocal sweat chloride levels (e.g., McGinniss_2005). It has also been reported as a complex allele in cis with p.H939R and another disease causing CF variant in trans (i.e., compound heterozygous genotype) in patients with CF (at least four ascertainments) and CFTR-RD (at least one ascertainment) (e.g., Polizzi_2011, Diana_2016, Paganin_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 8% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 26911355, 16189704, 25898134, 21931512). ClinVar contains an entry for this variant (Variation ID: 53578). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2024	The p.H949L variant (also known as c.2846A>T), located in coding exon 17 of the CFTR gene, results from an A to T substitution at nucleotide position 2846. The histidine at codon 949 is replaced by leucine, an amino acid with similar properties. This variant was detected in an individual with atypical cystic fibrosis (CF), whose symptoms included sinus problems and inconclusive sweat test results (McGinniss MJ et al. Hum. Genet., 2005 Dec;118:331-8). This variant was also reported as part of a complex allele [H939R;H949L] in five individuals from an Italian CF cohort, all of whom had another CFTR variant identified as in trans; four of the cases had classic CF phenotypes, and one had CFTR-related disease (Polizzi A et al. Genet. Mol. Biol., 2011 Jul;34:416-20). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 08, 2020	CFTR c.2846A>T has been identified an individual with an equivocal sweat chloride concentration. There is an entry in ClinVar for this variant and it (rs397508444) is rare (<0.1%) in a large population dataset (gnomAD: 5/282786 total alleles; 0.0018%; no homozygotes). Three bioinformatic tools queried predict that this substitution would probably be damaging and the histidine residue at this position is evolutionarily conserved across all species assessed. c.2846A>T has been reported as part of a complex allele on the same chromosome as c.2816A>G in multiple individuals. This patient does not carry this complex allele, as only c.2846A>T is present. Due to insufficient evidence, we consider the clinical significance of c.2846C>T to be uncertain at this time. -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-9.3	D;.;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.90
MutPred		0.82		Gain of catalytic residue at H949 (P = 0.0077);.;.;.;.;
MVP		1.0
MPC		0.015
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.98

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: rs397508444; hg19: chr7-117243774;