NM_000492.4:c.3161A>T

Variant names:

• chr7-117611602-A-T
• rs1417435640
• NM_000492.4:c.3161A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000492.4(CFTR):​c.3161A>T​(p.His1054Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,302 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H1054D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.27

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 60) in uniprot entity CFTR_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) 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 chr7-117611601-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3161A>T	p.His1054Leu	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3161A>T	p.His1054Leu	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459302 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726096

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 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.3161A>T (p.His1054Leu) 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 was absent in 250518 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3161A>T in individuals affected with Cystic Fibrosis or other CFTR-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. A different missense variant affecting the same amino acid (c.3160C>G, p.H1054D) has been classified as pathogenic, suggesting His1054 may be important for CFTR function. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with leucine at codon 1054 of the CFTR protein (p.His1054Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 526017). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant disrupts the p.His1054 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7505690, 15463882; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

CFTR-related disorder Uncertain:1

Sep 23, 2020

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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;.;.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.1	D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.96
MutPred		0.66		Loss of disorder (P = 0.0513);.;.;.;.;
MVP		1.0
MPC		0.0057
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1417435640; hg19: chr7-117251656;