rs73715573

Variant names:

• chr7-117548630-T-G
• rs73715573
• NM_000492.4:c.1210-11T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117548630-T-G
• chr7-117548630-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_000492.4(CFTR):​c.1210-11T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,536,052 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (27 hom.)
• Consequence: CFTR NM_000492.4 intron
• Scores: Splicing: ADA: 0.9867
• Clinical Significance: Pathogenic/Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:20 U:1 O:1
• Conservation: PhyloP100: 0.236
• Publications: 16 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: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 7-117548630-T-G is Pathogenic according to our data. Variant chr7-117548630-T-G is described in ClinVar as Pathogenic/Likely_pathogenic|other. ClinVar VariationId is 178713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00941 (1340/142364) while in subpopulation EAS AF = 0.0252 (117/4640). AF 95% confidence interval is 0.0215. There are 10 homozygotes in GnomAd4. There are 654 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 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.1210-11T>G		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6091A>C		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1340 AN: 142252 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0123

GnomAD2 exomes AF: 0.00861 AC: 2046 AN: 237638 AF XY: 0.00857

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00831

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0202

Gnomad FIN exome AF: 0.000763

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.00712

GnomAD4 exome AF: 0.00983 AC: 13696 AN: 1393688 Hom.: 27 Cov.: 37 AF XY: 0.00984 AC XY: 6824 AN XY: 693280

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

African (AFR) AF: 0.00356 AC: 108 AN: 30356

American (AMR) AF: 0.00895 AC: 383 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 945 AN: 24824

East Asian (EAS) AF: 0.0143 AC: 554 AN: 38730

South Asian (SAS) AF: 0.00990 AC: 832 AN: 84064

European-Finnish (FIN) AF: 0.00128 AC: 64 AN: 50100

Middle Eastern (MID) AF: 0.0169 AC: 95 AN: 5620

European-Non Finnish (NFE) AF: 0.00933 AC: 9894 AN: 1059952

Other (OTH) AF: 0.0143 AC: 821 AN: 57256

⚠️ 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: 0.00941 AC: 1340 AN: 142364 Hom.: 10 Cov.: 32 AF XY: 0.00942 AC XY: 654 AN XY: 69436

African (AFR) AF: 0.00319 AC: 124 AN: 38818

American (AMR) AF: 0.0134 AC: 189 AN: 14136

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 158 AN: 3286

East Asian (EAS) AF: 0.0252 AC: 117 AN: 4640

South Asian (SAS) AF: 0.0125 AC: 55 AN: 4414

European-Finnish (FIN) AF: 0.00131 AC: 13 AN: 9912

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.0103 AC: 657 AN: 64050

Other (OTH) AF: 0.0122 AC: 24 AN: 1970

Alfa AF: 0.0132 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	1	-	Cystic fibrosis (12)
5	-	-	not provided (6)
1	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.8
DANN	Benign	0.86
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.080		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: rs73715573; hg19: chr7-117188684; COSMIC: COSV99135863;