NM_000492.4:c.3367+37G>A

Variant names:

• chr7-117611845-G-A
• rs137854873
• NM_000492.4:c.3367+37G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.3367+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,476,608 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (15 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0880
• Publications: 2 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-117611845-G-A is Benign according to our data. Variant chr7-117611845-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3367+37G>A		intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4384C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3367+37G>A		intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.3367+37G>A		intron	N/A	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.3277+37G>A		intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 335 AN: 151430 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00389

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00216 AC: 484 AN: 224434 AF XY: 0.00222

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.000994

Gnomad ASJ exome AF: 0.000518

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00338 AC: 4478 AN: 1325062 Hom.: 15 Cov.: 19 AF XY: 0.00329 AC XY: 2186 AN XY: 665428

African (AFR) AF: 0.000359 AC: 11 AN: 30618

American (AMR) AF: 0.00112 AC: 48 AN: 42944

Ashkenazi Jewish (ASJ) AF: 0.000436 AC: 11 AN: 25208

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38636

South Asian (SAS) AF: 0.00155 AC: 128 AN: 82424

European-Finnish (FIN) AF: 0.00201 AC: 100 AN: 49718

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5452

European-Non Finnish (NFE) AF: 0.00401 AC: 3983 AN: 994248

Other (OTH) AF: 0.00340 AC: 190 AN: 55814

GnomAD4 genome AF: 0.00221 AC: 335 AN: 151546 Hom.: 0 Cov.: 31 AF XY: 0.00195 AC XY: 144 AN XY: 74016

African (AFR) AF: 0.000629 AC: 26 AN: 41318

American (AMR) AF: 0.00105 AC: 16 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4798

European-Finnish (FIN) AF: 0.00124 AC: 13 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00389 AC: 264 AN: 67884

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00204

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cystic fibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.28
PhyloP100		-0.088
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	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: rs137854873; hg19: chr7-117251899;