NM_000492.4:c.743+40A>G

Variant names:

• chr7-117535451-A-G
• rs1800502
• NM_000492.4:c.743+40A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.743+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,595,360 control chromosomes in the GnomAD database, including 2,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (148 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1972 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.207
• Publications: 9 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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=-0.88).
• BP6: Variant 7-117535451-A-G is Benign according to our data. Variant chr7-117535451-A-G is described in ClinVar as Benign. ClinVar VariationId is 256256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.743+40A>G		intron	N/A	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.743+40A>G		intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.743+40A>G		intron	N/A	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.653+40A>G		intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5551 AN: 151504 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.0751

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0600

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0375

GnomAD2 exomes AF: 0.0392 AC: 9759 AN: 248686 AF XY: 0.0415

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0524

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0499 AC: 71992 AN: 1443742 Hom.: 1972 Cov.: 28 AF XY: 0.0499 AC XY: 35874 AN XY: 719270

African (AFR) AF: 0.00781 AC: 257 AN: 32904

American (AMR) AF: 0.0195 AC: 867 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 1116 AN: 25880

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39294

South Asian (SAS) AF: 0.0436 AC: 3745 AN: 85834

European-Finnish (FIN) AF: 0.0580 AC: 3059 AN: 52772

Middle Eastern (MID) AF: 0.0510 AC: 288 AN: 5650

European-Non Finnish (NFE) AF: 0.0543 AC: 59613 AN: 1097340

Other (OTH) AF: 0.0510 AC: 3040 AN: 59580

GnomAD4 genome AF: 0.0366 AC: 5554 AN: 151618 Hom.: 148 Cov.: 32 AF XY: 0.0364 AC XY: 2693 AN XY: 74060

African (AFR) AF: 0.00896 AC: 370 AN: 41302

American (AMR) AF: 0.0268 AC: 407 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.0459 AC: 159 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4812

European-Finnish (FIN) AF: 0.0600 AC: 624 AN: 10408

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3652 AN: 67940

Other (OTH) AF: 0.0371 AC: 78 AN: 2102

Alfa AF: 0.0451 Hom.: 42

Bravo AF: 0.0330

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:3

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Apr 27, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.97
DANN	Benign	0.32
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800502; hg19: chr7-117175505;