NM_000492.4:c.1584+3867delA

Variant names:

• chr7-117563520-GA-G
• rs4148707
• NM_000492.4:c.1584+3867delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000492.4(CFTR):​c.1584+3867delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 151,922 control chromosomes in the GnomAD database, including 139 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.037 (139 hom., cov: 32)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 1 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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0372 (5650/151922) while in subpopulation AFR AF = 0.0455 (1885/41438). AF 95% confidence interval is 0.0438. There are 139 homozygotes in GnomAd4. There are 3013 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 139 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1584+3867delA		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.161+995delT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1584+3866delA		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1584+3866delA		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1584+3866delA		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5639 AN: 151804 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0240

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0372 AC: 5650 AN: 151922 Hom.: 139 Cov.: 32 AF XY: 0.0406 AC XY: 3013 AN XY: 74244

African (AFR) AF: 0.0455 AC: 1885 AN: 41438

American (AMR) AF: 0.0157 AC: 240 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5162

South Asian (SAS) AF: 0.0314 AC: 151 AN: 4810

European-Finnish (FIN) AF: 0.115 AC: 1216 AN: 10558

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2025 AN: 67926

Other (OTH) AF: 0.0285 AC: 60 AN: 2108

Alfa AF: 0.0345 Hom.: 17

Bravo AF: 0.0294

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs4148707; hg19: chr7-117203574;