chr7-117530953-G-T

Variant names:

• chr7-117530953-G-T
• rs113993958
• NM_000492.4:c.328G>T
• CFTR p.Asp110Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_ModeratePP5

The NM_000492.4(CFTR):c.328G>T (p.Asp110Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,162 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000241. 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 (no review stars). 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)

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000241 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 moderate.
	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 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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>T p.Asp110Tyr	missense	Exon 4 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.328G>Tp.Asp110Tyr

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>T p.Asp110Tyr	missense	Exon 4 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.328G>T p.Asp110Tyr	missense	Exon 4 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.328G>T p.Asp110Tyr	missense	Exon 4 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.328G>Tp.Asp110Tyr

Exon rankExon 4 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.328G>Tp.Asp110Tyr

Exon rankExon 4 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.328G>Tp.Asp110Tyr

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: 0.00000398	AC:1	Hom:	AN:251100	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152162	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	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
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:13006	Cov:

Showing 7 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Cystic fibrosis (4)
1	1	-	CFTR-related disorder (2)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	not provided (1)
1	-	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Uncertain	2.1	M
PhyloP100	Pathogenic	9.5
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.89
VESM-3B	Benign	-8.2

Showing 28 of 28 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