7-117530953-G-C

Variant names:

• chr7-117530953-G-C
• rs113993958
• NM_000492.4:c.328G>C
• CFTR p.Asp110His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.328G>C (p.Asp110His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000167 (AC=27) in the gnomAD database across 1,613,670 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000611. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.52). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV001589600: Experimental studies have shown that this missense change affects CFTR function (PMID:11278813, 23891399)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D110N: Likely_pathogenic (ClinVar VariationId 553436, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D110?: not_provided (ClinVar VariationId 53706); p.D110= (synonymous): Likely_benign (ClinVar VariationId 1730061, 1 star); p.D110E: drug_response (ClinVar VariationId 53714, 3 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Cystic fibrosis (cf).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:19 O:2
• Conservation: PhyloP100: 9.52
• Publications: 89 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):

• congenital bilateral aplasia of vas deferens from CFTR mutation

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women's Health, ClinGen, Natera, 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001589600: Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 23891399).; SCV002611948: Functional data showed a reduced level of CFTR protein and 9% chloride activity compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Another study suggested that this mutation disrupts the chloride channel activity by destabilizing the open state of the CFTR protein (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54).; SCV000917200: A functional study showed that baseline chloride transport in CFTR-D110H transfected FRT cells was 9.1% of that in WT-CFTR transfected FRT cells (Van Goor_2013), indicating that D110H significantly affects normal function of CFTR.
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 18 pathogenic, 0 benign (OR vs. background: 185.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000611 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D110N: Likely_pathogenic (ClinVar VariationId 553436, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.D110?: not_provided (ClinVar VariationId 53706); p.D110= (synonymous): Likely_benign (ClinVar VariationId 1730061, 1 star); p.D110E: drug_response (ClinVar VariationId 53714, 3 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (19/19 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR NM_000492.4	MANE Select	c.328G>C p.Asp110His	missense	Exon 4 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.328G>Cp.Asp110His

Exon rankExon 4 of 27

missense

Prot: NP_000483.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR ENST00000003084.11	TSL:1MANE Select	c.328G>C p.Asp110His	missense	Exon 4 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.328G>C p.Asp110His	missense	Exon 4 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.328G>C p.Asp110His	missense	Exon 4 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.328G>Cp.Asp110His

Exon rankExon 4 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.328G>Cp.Asp110His

Exon rankExon 4 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.328G>Cp.Asp110His

Exon rankExon 4 of 26

missense

Prot: ENSP00000559265.1UniProt: A0ACI8SBR8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152162	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251100	Cov:
GnomAD4 exome	AF: 0.0000178	AC:26	Hom:0	AN:1461508	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152162	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:5	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:153998	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000297	AC:2	Hom:0	AN:6724	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.000119	5	41958	0.0000449	3	66882
SCHEMA(Schizophrenia)	0.0000129	1	77666	0.0000359	5	139300

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic; drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Cystic fibrosis (10)
2	-	-	CFTR-related disorder (2)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	Hereditary pancreatitis (1)
1	-	-	not specified (1)
-	-	-	ivacaftor response - Efficacy (1)
-	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-9.9
GPN-Star score	N/A	9.9
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Uncertain	2.1	M
PhyloP100	Pathogenic	9.5
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.85
VESM-3B	Benign	-7.1

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs113993958;

hg19: chr7-117171007;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar