NM_000492.4:c.3140-4A>T

Variant names:

• chr7-117611577-A-T
• rs397508507
• NM_000492.4:c.3140-4A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000492.4(CFTR):​c.3140-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 splice_region, intron
• Scores: Splicing: ADA: 0.006408
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.923
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).

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.3140-4A>T		splice_region intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4652T>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3140-4A>T		splice_region intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.3140-4A>T		splice_region intron	N/A	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.3050-4A>T		splice_region intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1406714 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 703358

African (AFR) AF: 0.00 AC: 0 AN: 32392

American (AMR) AF: 0.00 AC: 0 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 84896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062396

Other (OTH) AF: 0.00 AC: 0 AN: 58564

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		0.92
PromoterAI		-0.0050	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0064
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 8

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

Other links and lift over

dbSNP: rs397508507; hg19: chr7-117251631;