rs10234329

Variant names:

• chr7-117668151-A-C
• rs10234329
• NM_000492.4:c.*1043A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000492.4(CFTR):​c.*1043A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 152,318 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (38 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.306
• Publications: 8 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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-117668151-A-C is Benign according to our data. Variant chr7-117668151-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 358746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2169/152318) while in subpopulation AFR AF = 0.0313 (1300/41558). AF 95% confidence interval is 0.0299. There are 38 homozygotes in GnomAd4. There are 1086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.*1043A>C		3_prime_UTR	Exon 27 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.*1043A>C		3_prime_UTR	Exon 27 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.*1043A>C		3_prime_UTR	Exon 27 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.*1043A>C		3_prime_UTR	Exon 26 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2151 AN: 152200 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.0129

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0142 AC: 2169 AN: 152318 Hom.: 38 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74468

African (AFR) AF: 0.0313 AC: 1300 AN: 41558

American (AMR) AF: 0.00575 AC: 88 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4830

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00619 AC: 421 AN: 68038

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0120 Hom.: 8

Bravo AF: 0.0138

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cystic fibrosis (2)
-	-	2	not provided (2)
-	-	1	CFTR-related disorder (1)
-	-	1	Hereditary pancreatitis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10234329; hg19: chr7-117308205;