7-117531068-T-C

Variant names:

• chr7-117531068-T-C
• rs35516286
• NM_000492.4:c.443T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1 PM5 PP2 BP4_Strong BP6 BS2_Supporting

The NM_000492.4(CFTR):​c.443T>C​(p.Ile148Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,710 control chromosomes in the GnomAD database, including 12 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. I148N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 7.61
• Publications: 93 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117531068-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53949.
• 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=0.01625809).
• BP6: Variant 7-117531068-T-C is Benign according to our data. Variant chr7-117531068-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38850.
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.443T>C	p.Ile148Thr	missense	Exon 4 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.443T>C	p.Ile148Thr	missense	Exon 4 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.443T>C	p.Ile148Thr	missense	Exon 4 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.443T>C	p.Ile148Thr	missense	Exon 4 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00178 AC: 445 AN: 250526 AF XY: 0.00222

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00153 AC: 2229 AN: 1461452 Hom.: 12 Cov.: 31 AF XY: 0.00173 AC XY: 1260 AN XY: 727004

African (AFR) AF: 0.000239 AC: 8 AN: 33470

American (AMR) AF: 0.00141 AC: 63 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00648 AC: 559 AN: 86218

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53384

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5762

European-Non Finnish (NFE) AF: 0.00131 AC: 1453 AN: 1111820

Other (OTH) AF: 0.00164 AC: 99 AN: 60376

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74438

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.000589 AC: 9 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4814

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68002

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00155 Hom.: 3

Bravo AF: 0.00117

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	9	Cystic fibrosis (11)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	1	-	CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.69	N
PhyloP100		7.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.57
Sift	Benign	0.35	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.29	B
Vest4		0.82
MVP		1.0
MPC		0.0038
ClinPred		0.044	T
GERP RS		5.7
Varity_R		0.45
gMVP		0.91
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35516286; hg19: chr7-117171122;