rs4727853

Variant names:

• chr7-117548682-C-A
• rs4727853
• NM_000492.4:c.1251C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117548682-C-A
• chr7-117548682-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_000492.4(CFTR):​c.1251C>A​(p.Asn417Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N417S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.0730
• Publications: 25 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: Likely_benign. The variant received -4 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004736215).
• BP6: Variant 7-117548682-C-A is Benign according to our data. Variant chr7-117548682-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193592.

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.1251C>A	p.Asn417Lys	missense	Exon 10 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6143G>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.1251C>A	p.Asn417Lys	missense	Exon 10 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1251C>A	p.Asn417Lys	missense	Exon 10 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1161C>A	p.Asn387Lys	missense	Exon 9 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 1754 AN: 85878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00709

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.0634

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0276

GnomAD2 exomes AF: 0.00583 AC: 1117 AN: 191728 AF XY: 0.00515

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000284

Gnomad ASJ exome AF: 0.000568

Gnomad EAS exome AF: 0.000202

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00117 AC: 1287 AN: 1104044 Hom.: 0 Cov.: 38 AF XY: 0.00117 AC XY: 647 AN XY: 554234

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

African (AFR) AF: 0.00161 AC: 40 AN: 24822

American (AMR) AF: 0.00160 AC: 60 AN: 37388

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 37 AN: 19796

East Asian (EAS) AF: 0.00194 AC: 55 AN: 28304

South Asian (SAS) AF: 0.00143 AC: 108 AN: 75692

European-Finnish (FIN) AF: 0.00350 AC: 132 AN: 37678

Middle Eastern (MID) AF: 0.00112 AC: 5 AN: 4456

European-Non Finnish (NFE) AF: 0.000931 AC: 774 AN: 831160

Other (OTH) AF: 0.00170 AC: 76 AN: 44748

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0204 AC: 1750 AN: 85950 Hom.: 0 Cov.: 31 AF XY: 0.0230 AC XY: 965 AN XY: 42044

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

African (AFR) AF: 0.0168 AC: 384 AN: 22924

American (AMR) AF: 0.0241 AC: 196 AN: 8144

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 22 AN: 2070

East Asian (EAS) AF: 0.0191 AC: 52 AN: 2726

South Asian (SAS) AF: 0.0202 AC: 50 AN: 2474

European-Finnish (FIN) AF: 0.0665 AC: 364 AN: 5472

Middle Eastern (MID) AF: 0.0379 AC: 5 AN: 132

European-Non Finnish (NFE) AF: 0.0159 AC: 640 AN: 40234

Other (OTH) AF: 0.0273 AC: 33 AN: 1210

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0901 Hom.: 0

ExAC AF: 0.0193 AC: 2338

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Cystic fibrosis (4)
-	2	2	not provided (4)
-	-	1	CFTR-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.41
DANN	Benign	0.23
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.49	N
PhyloP100		-0.073
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.33	N
REVEL	Uncertain	0.39
Sift	Benign	0.51	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.43		Gain of ubiquitination at N417 (P = 0.017)
MPC		0.0038
ClinPred		0.0033	T
GERP RS		-4.1
Varity_R		0.18
gMVP		0.47
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4727853; hg19: chr7-117188736; COSMIC: COSV50040523;