7-117548629-T-TGTG

Variant names:

Variant summary

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

The NM_000492.4(CFTR):c.1210-12_1210-11insGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,491,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

CFTR
NM_000492.4 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 0.236

Publications

0 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:

Genome browser will be placed here

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.1210-12_1210-11insGTG		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6091_222-6090insCAC		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1210-12_1210-11insGTG	intron	N/A	ENSP00000003084.6
CFTR	ENST00000699602.1		c.1210-12_1210-11insGTG	intron	N/A	ENSP00000514471.1
CFTR	ENST00000426809.5	TSL:5	c.1120-12_1120-11insGTG	intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes

AF:

0.0000901

AC:

AN:

133130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00216

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000820

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000898

AC:

AN:

211464

AF XY:

0.0000696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00125

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000884

AC:

120

AN:

1357984

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

676374

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29712

American (AMR)

AF:

0.00

AC:

AN:

42844

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

23586

East Asian (EAS)

AF:

0.00

AC:

AN:

38726

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50168

Middle Eastern (MID)

AF:

0.000364

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1028688

Other (OTH)

AF:

0.000324

AC:

AN:

55562

⚠️ 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: 0.303

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:

0.0000901

AC:

AN:

133216

Hom.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

64656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34560

American (AMR)

AF:

0.00

AC:

AN:

14154

Ashkenazi Jewish (ASJ)

AF:

0.00216

AC:

AN:

3234

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000820

AC:

AN:

60982

Other (OTH)

AF:

0.00

AC:

AN:

1878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2

Jul 11, 2025

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This individual carries the 6T variant in the CFTR T tract. Variants in the T tract alone are not thought to be CF-causing variants; however, their likelihood of acting as such is influenced by another region in the CFTR gene called the TG tract. The TG tract typically occurs in three forms: 11TG, 12TG, or 13TG. This individual has 6T/13TG. This variant has been reported in individuals with features of CF and in ClinVar (Variation ID: 1043026). It (rs4148705) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomADv4.1.0: 68/26820 alleles; 0.25%, no homozygotes). Three bioinformatic tools predicts that this intronic variant would not significantly affect normal exon 10 (legacy exon 9) splicing, although this has not been confirmed experimentally to our knowledge. We consider the clinical significance of 6T/13TG to be uncertain at this time, although it is unlikely to be CF-causing and could be a variant of varying clinical consequence (VCC).

Oct 10, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant consists of 13 TG and 6 T nucleotide repeats and is located in intron 9 of the CFTR gene. While this variant is present in population databases (rs397843667), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a CFTR-related disease. However, it occurs on the opposite chromosome (in trans) from a pathogenic variant in CFTR in an unaffected individual (Invitae database). Considering that biallelic pathogenic variants in CFTR are expected to cause cystic fibrosis or congenital bilateral absence of the vas deferens (CBAVD), this evidence indicates this TG[13]T[6] allele is not a primary cause of disease. Different TG variants, TG[11]T6 and TG[12]T[6], have been reported in individuals affected with bronchial asthma and chronic bronchitis, as well as healthy individuals (PMID: 18350634, 23554779). A different TG13 variant, TG[13]T[5] is known to induce skipping of exon 9, and has been observed in individuals affected with CBAVD and cystic fibrosis (PMID: 10556281, 14685937), while the TG[13]T[7] variant has only been reported in controls (PMID: 24551851). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided

Uncertain:1

Dec 14, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFTR-related disorder

Benign:1

Mar 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over