Genetic Variant NM_000492.4:c.1210-17_1210-12dupGTGTGT (chr7-117548606-A-ATGTGTG) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000492.4(CFTR):c.1210-17_1210-12dupGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

CFTR
NM_000492.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0650

Publications

2 publications found

Variant links:

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 links:

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

CFTR-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.1210-17_1210-12dupGTGTGT		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6073_222-6068dupCACACA		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1210-35_1210-34insTGTGTG	intron	N/A	ENSP00000003084.6
CFTR	ENST00000699602.1		c.1210-35_1210-34insTGTGTG	intron	N/A	ENSP00000514471.1
CFTR	ENST00000426809.5	TSL:5	c.1120-35_1120-34insTGTGTG	intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

143508

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000764

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000206

Gnomad SAS

AF:

0.000224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000617

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000868

AC:

119

AN:

1370514

Hom.:

Cov.:

AF XY:

0.0000939

AC XY:

AN XY:

681286

show subpopulations

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

African (AFR)

AF:

0.0000316

AC:

AN:

31670

American (AMR)

AF:

0.0000242

AC:

AN:

41254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24034

East Asian (EAS)

AF:

0.000109

AC:

AN:

36852

South Asian (SAS)

AF:

0.000124

AC:

AN:

80644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

0.0000976

AC:

102

AN:

1044586

Other (OTH)

AF:

0.0000177

AC:

AN:

56408

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000627

AC:

AN:

143608

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

69794

show subpopulations

African (AFR)

AF:

0.0000762

AC:

AN:

39392

American (AMR)

AF:

0.00

AC:

AN:

14548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3294

East Asian (EAS)

AF:

0.000206

AC:

AN:

4848

South Asian (SAS)

AF:

0.000225

AC:

AN:

4444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000618

AC:

AN:

64770

Other (OTH)

AF:

0.00

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.065

La Branchor

0.64

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over