rs1800076

Variant names:

• chr7-117509093-G-A
• rs1800076
• NM_000492.4:c.224G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117509093-G-A
• chr7-117509093-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000492.4(CFTR):​c.224G>A​(p.Arg75Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,611,610 control chromosomes in the GnomAD database, including 1,043 homozygotes. In-silico tool predicts 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. R75L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (44 hom., cov: 33)
  • Exomes 𝑓: 0.031 (999 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:17 O:2
• Conservation: PhyloP100: 7.71
• Publications: 123 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 -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_000492.4
• 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=0.011586249).
• BP6: Variant 7-117509093-G-A is Benign according to our data. Variant chr7-117509093-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35839.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2830/152290) while in subpopulation NFE AF = 0.0342 (2325/68014). AF 95% confidence interval is 0.033. There are 44 homozygotes in GnomAd4. There are 1183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.224G>A	p.Arg75Gln	missense	Exon 3 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.224G>A	p.Arg75Gln	missense	Exon 3 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.224G>A	p.Arg75Gln	missense	Exon 3 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.224G>A	p.Arg75Gln	missense	Exon 3 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2830 AN: 152172 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.0154 AC: 3874 AN: 250966 AF XY: 0.0153

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00437

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0313 AC: 45647 AN: 1459320 Hom.: 999 Cov.: 29 AF XY: 0.0299 AC XY: 21694 AN XY: 726240

African (AFR) AF: 0.00493 AC: 165 AN: 33442

American (AMR) AF: 0.00731 AC: 327 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 121 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39654

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86212

European-Finnish (FIN) AF: 0.00454 AC: 241 AN: 53132

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5756

European-Non Finnish (NFE) AF: 0.0386 AC: 42817 AN: 1109988

Other (OTH) AF: 0.0295 AC: 1780 AN: 60290

GnomAD4 genome AF: 0.0186 AC: 2830 AN: 152290 Hom.: 44 Cov.: 33 AF XY: 0.0159 AC XY: 1183 AN XY: 74466

African (AFR) AF: 0.00739 AC: 307 AN: 41566

American (AMR) AF: 0.00843 AC: 129 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10608

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0342 AC: 2325 AN: 68014

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.0258 Hom.: 277

Bravo AF: 0.0187

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0475 AC: 183

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.0308 AC: 265

ExAC AF: 0.0153 AC: 1863

Asia WGS AF: 0.00318 AC: 11 AN: 3472

EpiCase AF: 0.0323

EpiControl AF: 0.0296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	7	Cystic fibrosis (9)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	1	1	CFTR-related disorder (2)
-	-	1	Hereditary pancreatitis (2)
-	1	-	Lung disease, non-specific (1)
-	-	-	Abnormality of the pancreas (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MPC		0.0066
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.80
gMVP		0.91
Mutation Taster		=36/64	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1800076; hg19: chr7-117149147; COSMIC: COSV50052290; COSMIC: COSV50052290;