chr7-117548629-T-TG

Variant names:

• chr7-117548629-T-TG
• rs4148705
• NM_000492.4:c.1210-12_1210-11insG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000492.4(CFTR):​c.1210-12_1210-11insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 133,216 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.236
• 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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 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.1210-12_1210-11insG		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6091_222-6090insC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1210-12_1210-11insG		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1210-12_1210-11insG		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1210-12_1210-11insG		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 190 AN: 133130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.00572

Gnomad FIN AF: 0.000128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000541

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000393 AC: 83 AN: 211464 AF XY: 0.000365

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.000394

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00108 AC: 1463 AN: 1357602 Hom.: 1 Cov.: 37 AF XY: 0.00108 AC XY: 731 AN XY: 676144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000909 AC: 27 AN: 29704

American (AMR) AF: 0.00224 AC: 96 AN: 42768

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 7 AN: 23606

East Asian (EAS) AF: 0.00963 AC: 372 AN: 38644

South Asian (SAS) AF: 0.00313 AC: 260 AN: 83100

European-Finnish (FIN) AF: 0.000120 AC: 6 AN: 50168

Middle Eastern (MID) AF: 0.000728 AC: 4 AN: 5498

European-Non Finnish (NFE) AF: 0.000598 AC: 615 AN: 1028564

Other (OTH) AF: 0.00137 AC: 76 AN: 55550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00143 AC: 190 AN: 133216 Hom.: 2 Cov.: 32 AF XY: 0.00156 AC XY: 101 AN XY: 64656

African (AFR) AF: 0.000781 AC: 27 AN: 34560

American (AMR) AF: 0.00254 AC: 36 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3234

East Asian (EAS) AF: 0.0133 AC: 68 AN: 5120

South Asian (SAS) AF: 0.00573 AC: 25 AN: 4360

European-Finnish (FIN) AF: 0.000128 AC: 1 AN: 7816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000541 AC: 33 AN: 60982

Other (OTH) AF: 0.00 AC: 0 AN: 1878

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not specified (3)
-	1	-	CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4148705; hg19: chr7-117188683;