chr7-117652876-A-C

Variant names:

• chr7-117652876-A-C
• rs397508636
• NM_000492.4:c.3908A>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000492.4(CFTR):​c.3908A>C​(p.Asn1303Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1303K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.61
• Publications: 6 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117652877-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7136.Status of the report is practice_guideline, 4 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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.3908A>C	p.Asn1303Thr	missense	Exon 24 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.3908A>C	p.Asn1303Thr	missense	Exon 24 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.3902A>C	p.Asn1301Thr	missense	Exon 24 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.3818A>C	p.Asn1273Thr	missense	Exon 23 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445504 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 719968

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5084

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098786

Other (OTH) AF: 0.00 AC: 0 AN: 59740

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1303T variant (also known as c.3908A>C), located in coding exon 24 of the CFTR gene, results from an A to C substitution at nucleotide position 3908. The asparagine at codon 1303 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not provided Uncertain:1

Jul 17, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.3908A>C (p.Asn1303Thr) variant involves the alteration of a conserved nucleotide located in the P-loop containing nucleoside triphosphate hydrolase domain and ABC transporter-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 120262 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Variant involving the same nucleotide and/or same codon such as c.3908A>T/p.N1303I, c.3907A>C/N1303H, c.3909C>G/N1303K have been reported in multiple affected individuals, suggesting this is a mutation hotspot. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance-possibly pathogenic until additional information becomes available.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of phosphorylation at N1303 (P = 0.0419)
MVP		1.0
MPC		0.017
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		0.016	Neutral
Varity_R		0.94
gMVP		0.94
Mutation Taster		=14/86	disease causing

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: rs397508636; hg19: chr7-117292930;