NM_000492.4:c.-34C>T

Variant names:

• chr7-117480061-C-T
• rs756314710
• NM_000492.4:c.-34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000492.4(CFTR):​c.-34C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 2.23
• Publications: 4 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117480061-C-T is Pathogenic according to our data. Variant chr7-117480061-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552672.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_000483.3
	CFTR	NM_000492.4	MANE Select	c.-34C>T		5_prime_UTR	Exon 1 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	ENSP00000003084.6
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.-34C>T		5_prime_UTR	Exon 1 of 27	ENSP00000003084.6
	CFTR	ENST00000546407.1	TSL:1	n.166+4253C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250744 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454016 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723796

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104948

Other (OTH) AF: 0.00 AC: 0 AN: 60118

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Cystic fibrosis (4)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		2.2
PromoterAI		-0.052	Neutral
Mutation Taster		=45/255	disease causing (ClinVar)

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: rs756314710; hg19: chr7-117120115;