7-117530953-G-A

Variant names:

• chr7-117530953-G-A
• rs113993958
• NM_000492.4:c.328G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000492.4(CFTR):​c.328G>A​(p.Asp110Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D110E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) 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 chr7-117530955-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.328G>A	p.Asp110Asn	missense_variant	Exon 4 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.328G>A	p.Asp110Asn	missense_variant	Exon 4 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:1

Apr 07, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.328G>A (p.Asp110Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251100 control chromosomes. c.328G>A has been reported in the literature together with F508del in an individual affected with neonatal hypertrypsinaemia and intermediate sweat chloride values who was ultimately diagnosed with Cystic Fibrosis (Corbetta_2002). Different variants affecting the same codon have been classified as pathogenic by our lab (c.328G>C, p.Asp110His; c.328G>T, p.Asp110Tyr; c.330C>A, p.Asp110Glu), supporting the critical relevance of codon 110 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 23% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12133923, 38388235). ClinVar contains an entry for this variant (Variation ID: 553436). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 18, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D;.;.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.51	.;N;.;.;.;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.2	D;N;.;.;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.099	T;T;.;.;T;.
Sift4G	Pathogenic	0.0	D;T;.;.;T;.
Polyphen		0.21	.;B;.;.;.;.
Vest4		0.92
MutPred		0.82		.;Gain of ubiquitination at K114 (P = 0.0985);Gain of ubiquitination at K114 (P = 0.0985);Gain of ubiquitination at K114 (P = 0.0985);Gain of ubiquitination at K114 (P = 0.0985);Gain of ubiquitination at K114 (P = 0.0985);
MVP		0.99
MPC		0.0042
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs113993958; hg19: chr7-117171007;