NM_000492.4:c.1210-7_1210-6dupTT

Variant names:

• chr7-117548628-G-GTT
• rs1805177
• NM_000492.4:c.1210-7_1210-6dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1210-7_1210-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 142,512 control chromosomes in the GnomAD database, including 184 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (184 hom., cov: 31)
  • Exomes 𝑓: 0.030 (422 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.565
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 7-117548628-G-GTT is Benign according to our data. Variant chr7-117548628-G-GTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 161188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

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.1210-7_1210-6dupTT		splice_region intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6091_222-6090dupAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1210-13_1210-12insTT		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1210-13_1210-12insTT		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1210-13_1210-12insTT		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6243 AN: 142412 Hom.: 181 Cov.: 31

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.0101

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00275

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0324

GnomAD2 exomes AF: 0.0333 AC: 6825 AN: 205052 AF XY: 0.0330

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00153

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0305

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0299 AC: 42111 AN: 1406430 Hom.: 422 Cov.: 36 AF XY: 0.0295 AC XY: 20617 AN XY: 699778

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

African (AFR) AF: 0.0601 AC: 1857 AN: 30910

American (AMR) AF: 0.0111 AC: 476 AN: 42824

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 328 AN: 24450

East Asian (EAS) AF: 0.00584 AC: 224 AN: 38372

South Asian (SAS) AF: 0.0250 AC: 2081 AN: 83304

European-Finnish (FIN) AF: 0.102 AC: 5268 AN: 51444

Middle Eastern (MID) AF: 0.0151 AC: 84 AN: 5562

European-Non Finnish (NFE) AF: 0.0282 AC: 30192 AN: 1071904

Other (OTH) AF: 0.0278 AC: 1601 AN: 57660

⚠️ 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: 0.0439 AC: 6260 AN: 142512 Hom.: 184 Cov.: 31 AF XY: 0.0473 AC XY: 3286 AN XY: 69466

African (AFR) AF: 0.0664 AC: 2456 AN: 36962

American (AMR) AF: 0.0225 AC: 324 AN: 14400

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 52 AN: 3408

East Asian (EAS) AF: 0.00276 AC: 14 AN: 5074

South Asian (SAS) AF: 0.0343 AC: 156 AN: 4552

European-Finnish (FIN) AF: 0.119 AC: 1139 AN: 9606

Middle Eastern (MID) AF: 0.0180 AC: 5 AN: 278

European-Non Finnish (NFE) AF: 0.0311 AC: 2033 AN: 65380

Other (OTH) AF: 0.0367 AC: 72 AN: 1962

Alfa AF: 0.0101 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Cystic fibrosis (4)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1805177; hg19: chr7-117188682; COSMIC: COSV99137297;